Recent Advances in ADCs
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Last updated on 30th September 2024
Abstract
ADCs (Antibody-drug conjugates) represent an innovative class of chemotherapeutics, which combine the precision of monoclonal antibodies (mAbs) with potent cytotoxic agents. Each generation of ADC has steadily progressed closer to the goal of targeted cancer therapy, with enhanced efficacy and reduced off-target toxicity. Notably, there have been 11 FDA approvals, till date, and over 1,000 ADCs are currently in various stages of development. The momentum of the ADC field is underscored by several billion-dollar industry deals, and the global ADC sales exceeding $9 billion in the last year.
This review navigates the complex ADC landscape by focusing on critical aspects of ADCs, including their key features, mechanisms of action, bioconjugation techniques, and the selection of linkers, cytotoxins, and linker-payload combinations. The review provides an in-depth overview of approved and clinical candidates, while examining significant business activities, including mergers and acquisitions, offering a comprehensive resource on both the scientific and commercial landscapes of ADCs. It also addresses ADC toxicity mechanisms and reasons behind discontinuation of various clinical drugs, further explaining strategies to overcome these challenges and providing insights into the future direction of research and development of next-generation ADCs.
Introduction
After the initial success of auristatin and maytansinoid-based ADCs (Kadcyla®, Adcetris®), there were multiple setbacks in terms of project discontinuations and withdrawal of clinical candidates. The approval of Padcev®, Enhertu® and Trodelvy® in 2019-2020 renewed hope for the therapeutic applications of ADCs in oncology and other disease indications. Designed with chemistry to match the targets more precisely, rather than a one-size-fits all strategy, these ADCs have shown remarkable clinical outcomes. Enhertu and Trodelvy showed a 37%1 and 59%2 reduction in the risk of disease progression or death for patients with breast cancer respectively. Resurgence in the ADC space is highlighted by a significant rise in the number of ADCs (~270) undergoing clinical trials3, substantial business investments and a wave of mergers and acquisitions (M&A). Also, in terms of revenue, the global ADC market reached an estimated value of $9.7 billion in 2023 and is projected to exhibit a CAGR of 15.2% from 2023 to 2028.4
Even after 13 approvals globally and success of treatments like Kadcyla (with a median OS of 30.9 months; ORR of 43.6%)5 and Enhertu (with a median OS of 29.1 months; ORR of 62.0%)6 , the ADC landscape remains challenging. Discontinuation rates are still high across multiple payload mechanisms, notably auristatins, maytansinoids, and PBD-dimers. As of September 2024, 75 ADC projects have been discontinued3, and several other projects are currently inactive, highlighting the inherent complexities and difficulties involved in matching the linker-payload and mAb specifically to the target.
Off-target toxicity in ADCs can limit dosing to levels below those necessary for optimal anti-cancer efficacy. This toxicity may arise from factors such as target expression on healthy cells, premature drug release, and off-target binding. The maximum tolerated dose (MTD) thus needs to be lowered to prevent significant harm to the patient. However, reducing the dose below the optimal therapeutic range can lead to suboptimal cancer treatment. Even among FDA-approved ADCs, a considerable fraction of treated patients requires supportive care to manage ADC-associated toxicities, often leading to dose reductions, treatment delays, or discontinuations. The conventional “one-size-fits-all” or “copy-paste” approach, which focuses on repurposing established targets and linker-payload combinations, can frequently be unsuccessful. Achieving the right balance between efficacy and safety requires the careful design of ADCs, focusing on better target selection, improved linkers, and optimized payloads thus making its crucial to explore and implement diverse translational strategies in ADC development. Creating a focused approach based on past failures and successes can guide the development of an optimal clinical candidate. Since every cancer and target is unique the right combination would be required. The emergence of site-specific conjugation technologies and innovative payload-linker strategies, coupled with the identification of new target compounds, has fueled the evolution of ADCs over the past two decades, and is helping move the field towards fourth generation and beyond successes.
To address the challenge of high project discontinuation rates, a “data-driven approach” is essential. A thorough understanding of the mechanism of action, advancements, and obstacles in the field of ADCs can help making informed decisions and in effective progress of the drug development programs. It is imperative to embrace innovative approaches based on years of research data and leverage technological advancements to develop next-generation ADCs.
In this review, we offer an in-depth exploration of recent advancements in the field while covering essential aspects such as the mechanism of action, a summary of approved drugs and ongoing clinical studies, the underlying mechanisms of ADC toxicity, current research trends, and insights into the business landscape of ADCs. The technological progress discussed here holds promise for addressing challenges in drug discovery and advancing ADC development across established and emerging therapeutic areas.
The Evolution of Antibody-Drug Conjugates from Inception to Innovation
Figure 1. Timeline of Antibody-Drug Conjugates7
It has taken several decades from the inception of the concept of ADCs to its realization, signifying the process is highly complex as compared to small-molecules drugs. Development of a successful ADC candidate requires proper integration of the receptor (target), antibody, linker, and payload. Challenges in any of these components can lead to clinical failure and withdrawal of the drug programs. We will address each one of these key elements in detail in the later sections.
Figure 2: Anatomy of an ADC8
Ever since the development of the hybridoma technology (1975), the pace of research in this field has gained considerable momentum. Initial in vitro studies utilized antibodies conjugated to radioactive isotopes or cytotoxic drugs to target cancer cells. Issues such as low DAR (drug-to-antibody ratio), unstable linkers, and poor pharmacokinetics slowed down progress. The development of mAbs by Kohler and Milstein (1970) allowed the production of large volumes of a single antibody clone, with pre-selected specificity, enhancing its potential to be used for research and clinical applications.9 This paved the way for critical advances like humanization and production of engineered mAbs to recognize various target antigens for chemotherapy.10
In 1983, the first human trial of an ADC (anti-carcinoembryonic antigen antibody and vindesine), was deemed safe and effective in eight patients with advanced metastatic carcinomas.11,12, Gemtuzumab ozogamicin (Mylotarg), was the first FDA approved ADC (2000) targeting hematologic cancers with a CD33 monoclonal antibody conjugated to calicheamicin.13 A decade later, trastuzumab emtansine (Kadcyla®) was approved for treating HER2-positive breast cancer, demonstrating the potential of ADCs beyond hematologic malignancies.14
The approval of trastuzumab emtansine and its successful clinical outcomes catalyzed significant investments and excitement in ADC research. However, not all ADCs shared this success. Some faced substantial hurdles during clinical development and commercialization, including safety or efficacy concerns. For example, Mylotarg was withdrawn after subsequent trials failed to confirm its clinical benefit and highlighted safety issues, including high early death rates in group of patients who received the drug compared to those receiving standard chemotherapy alone.15 It was later reintroduced to the market in 2017 with an alteration in the dosage regime.16
Over three generations, ADC development has undergone significant changes driven by innovative technologies. Site-specific conjugation methods have enabled more precise control over the DAR, while maintaining the binding affinity and specificity of the antibody. Novel linkers and their associated triggers, designed to improve the specificity and safety of ADCs allow for the controlled release of cytotoxic drugs in the tumor microenvironment, minimizing off-target toxicity. Newer strategies include – Fe(II)-responsive linkers (respond to the higher levels of ferrous iron in tumors ) and enzyme-cleavable linkers (glycosidases and phosphatases), photo-responsive linkers (light exposure), bioorthogonal linkers (require biorthogonal cleavage pairs such as Cu(I)-BTTAA)17 and dual-enzyme cleavable linkers.18 Advances in antibody engineering and selection have also enhanced the binding affinity, and pharmacokinetics, increasing the potency and efficacy of the ADC.
Overall, these technological advancements have addressed many challenges in ADC development, highlighted by increase in the number of clinical trials and growing investments in the field.
Table 1: Comparison of different generations of ADCs7
First-generation ADCs | Second-generation ADCs | Third-generation ADCs | |
Antibodies | Mouse-original or chimeric humanized antibodies | Humanized antibodies | Fully humanized antibodies or Fabs |
Linkers | Unstable Monovalent Non-cleavable Acid-labile | Improved stability (Cleavable/ Non-cleavable) Monovalent | Stable in circulation |
Payloads | Low potency (duocarmycin, doxorubicin) | Improved potency (auristatins, maytansinoids) | Low potency (camptothecins & novel payloads like immunomodulators) |
Conjugation methods | Random Lysines | Random Lysines and Reduced Interchain Cysteines | Site-Specific Conjugation |
DAR | Heterogeneous (generally 0-8) | Heterogeneous (generally 4-8) | Homogenous (generally 2, 4, 8) |
Advantages | · Specific targeting · Slightly increased therapeutic window | · Improved specific targeting · More potent payloads · Lower immunogenicity | · Higher efficacy · Improved DAR and improved stability |
Disadvantages | · Heterogeneity · Lack of efficacy · Narrow therapeutic index · Off-target toxicity due to premature release of drug · High Immunogenicity | · Heterogeneity · Fast clearance for high DAR ADCs · Off-target toxicity (premature drug release) · Drug resistance | · Potential toxicity due to high potency payloads · Catabolism difference across species · Drug Resistance |
Examples of Approved ADCs | Mylotarg®, Besponsa® | Kadcyla®, Adcetris®, Padcev®, Elahere® | Enhertu®, Trodelvy® |
Mechanism of action of Antibody-Drug Conjugates
From the initial approval of Mylotarg in 2000 to the subsequent approvals of Adcetris (2011), Kadcyla (2013) and Besponsa (2017), the development of ADCs has experienced a slow start, suggestive of an extended and challenging learning phase.19 However, since 2019, the number of approved ADCs has more than doubled, with five approvals between 2019 and 2020, reflecting a significant advancement in the understanding of both the biology and chemistry of ADCs. Figure 1 highlights the five critical elements in the design of effective ADCs – target antigen; targeting moiety; linker; conjugation method; and cytotoxic payload.
Figure 3: Aspects of ADC Design10
Mechanistically, an ADC functions by binding to the target antigen on the cell surface, undergoing internalization through antigen-mediated endocytosis, and trafficking into the lysosome. Here the payload releases or is cleaved resulting in toxin-mediated chemotherapy.20 The ADC approach enhances specificity, thereby increasing therapeutic efficacy while minimizing toxicity and reducing the required dosage. Figure 4 below describes the steps that lead to ADC activity.
Figure 4: Mechanism of action of an ADC.8, 21, 22
Once the payload is released from the lysosome, the type of payload used will determine which cell death program is triggered. Figure 4 (A-H) highlights mechanisms of different payload types. Figure 4 – (A) DNA inhibitors; (B) Splicing inhibitors; (C) RNA polymerase inhibitor; (D) Protein Degrader; (E) Microtubule inhibitor; (F) Bcl-xL inhibitor; (G) Topoisomerase inhibitor; (H) NAMPT inhibitor
Strategies for Enhanced Efficacy and Safety in ADCs
Over the past few years, extensive research has focused on the five critical elements of ADC design.7 Numerous failures and successes in preclinical and clinical programs have led to the development of innovative strategies aimed at improving and advancing the chemistry of these elements to create next-generation ADCs.
Target Antigen
Recent advancements in ADC research are focused on identifying cell surface antigens that are either overexpressed or uniquely expressed on cancer cells. This approach aims to enhance treatment specificity and minimize toxicity concerns. Additionally, researchers are exploring targeting components of the tumor microenvironment, such as stromal cells or vasculature, to disrupt tumor growth and metastasis. Novel antibody formats enable simultaneous targeting of multiple antigens, enhancing the efficacy of ADCs.7 Tumor-associated glycoproteins, such as mucins23 and glycosylated proteins,24 are also gaining attention due to their specific expression patterns in tumors. Next-generation ADCs are being developed to target a wide array of cell-membrane receptors and proteins. The most explored target antigens are highlighted in Table 2.
Figure 5. Top disclosed ADC Targets3
Driver Oncogenes | HER2, EGFR | |
Target Antigens in tumor vasculature | EDB (Fibronectin, extra-domain B), ETB (Endothelium receptor), PSMA, VEGFR2, ROB04, Tissue Factor | |
Target Antigens in tumor stroma | Collagen IV, Periostin, Tenascin C | |
Target Antigens overexpressed in cancer cells | GPNMB, CD70, CD56 (NCAM), Trop-2 (TACSTD2), Folate receptor alpha, Tissue factor, ENPP3, p-Cadherin, Mesothelin, STEAP1, CEACAM5, Mucin1, Nectin 4, SLC44A4, PSMA, LIV1 (ZIP6), 5T4, SC-16, Guanylyl cylcase C, SLITRK6 | |
Target Antigens in hematological malignancies | CD30, CD22, CD79b, CD19, CD138, CD74, CD37, CD33, CD98 |
Targeting moiety
Antibodies used are exclusively of the IgG class (subclass IgG1, IgG2, IgG3, and IgG4) which have a unique profile with respect to the length of hinge region, the number of inter-chain disulfide bonds, and Fc-effector functions.
Figure 7. Immunoglobulin G (IgG) subtypes
Table 3. Comparison chart of IgG subtypes 3,26,27
IgG1 | IgG2 | IgG3 | IgG4 | |
Molecular mass (kD) | 146 | 146 | 170 | 146 |
Amino acids in hinge region | 15 | 12 | 62 | 12 |
Inter-heavy chain disulfide bonds | 2 | 4 | 11 | 2 |
Serum half-life | ~21 days | ~21 days | ~7 days | ~21 days |
Complement activation (C1q binding) | †† | † | ††† | ─ |
Specifications | Induces strong effector functions such as ADCC, ADCP & CDC by high binding affinity with Fc receptor | Potential for more conjugation sites (Increased cytotoxic payload) | More efficient at inducing tumor cell lysis | Ability to form half antibodies and swap fragments with other IgG4 units (hybrid bispecific compounds) |
Approved ADCs | Kadcyla®, Enhertu®, Trodelvy®, Adcetris®, Polivy®, Padcev®, Elahere®, Aidexi®, Ujvira™, Zynlonta®, Tivdak® | N/A | N/A | Mylotarg®, Besponsa® |
Candidates in clinical trial | 130 | 1 | N/A | 1 |
Hematologic indications account for 6 out of 13 approved ADCs, 3 of the remaining 7 ADCs targeting solid tumors work on treating breast cancer. However, inadequate penetration of tumor cells remains a concern limiting the drug’s efficacy for solid tumors. Research on alternative delivery systems like smaller targeting moieties can address the issue of poor penetration associated with large ADCs. Novel small-format drug conjugates are emerging at the preclinical stage, ranging from antibody-fragment drug conjugates (e.g., Fab, diabody, and scFv) to small protein scaffold-drug conjugates (e.g., Affibody, etc.) and are summarized in Table 4
Table 4. Small-format Drug Conjugates 28,29,30
Small -format drug conjugate | Mass | Structure | Advantage(s) | Drawback(s) |
150 kDa | Disulfide linked, two heavy + two light chains | Longer half-life and better drug accumulation at tumor site Ability to carry a higher load of drugs molecules Triggers immune-mediated effector functions (ADCC, CDC) | Drug resistance, off-target toxicity, low penetration | |
~ 75-80 kDa | Two fragments linked at hinge region | Better penetration than mAbs due to smaller size | Shorter half-life | |
~50 kDa | Disulfide linked, one heavy + one light chain | Block targets (receptors & signaling pathways) without cross-linking | Not very potent in vivo; modest reduction in tumor growth | |
~50 kDa | Two Fv domains connected by peptide linker | Rapid tumor penetration and accumulation due to smaller size | Higher dose needed to match potency of ADC | |
~25-27 kDa | Variable region of heavy and light chain joined by peptide linker | Successful for applications where time critical elimination was necessary | Low delivery rate | |
12.5 - 25 kDa | Lacks a light chain and heavy chain CH1 domain | Highly soluble and more stable than conventional antibodies | Slower and lesser internalization | |
10-25 kDa | Monomeric proteins with stable tertiary structures | Small size, high affinity, excellent specificity and stability | Requires use of protein engineering to ensure continuous exposure after dosing | |
~ 3.5-5 kDa | Protein motif containing 3 disulfide bridges (formed from pairs of cysteine residues) | 3 disulfide bonds provide remarkable stability against chemical denaturation, and proteolysis | Less potent than free payload | |
<5 kDa | Short chain of amino acids | Enhanced binding, diversity & capability to cross the cell membrane | Poor intrinsic pharmacokinetic properties of peptide; shorter half-life | |
~ 1.5 - 2 kDa | Intramolecular disulfide bond & bicyclization of the peptides | High affinity binding and specificity to protein target, greater conformational rigidity and metabolic stability | Poor physicochemical properties |
Linker Chemistry and Synthesis
More than 80% of the clinically approved ADCs (11 out of 13) and those in clinical development with disclosed linkers (172 out of 192) employ cleavable linkers.3 Cleavable linkers come in a variety of motifs and release mechanisms, but all have a bond that is custom designed to be broken at either a lower pH, with an enzyme or in the presence of thiols. The cleavable linkers will release a metabolite that can have membrane permeability. Membrane permeability usually will mean that the cytotoxin will have bystander activity, which is the ability to diffuse in neighboring cells and have an effect.
On the other hand, a non-cleavable linker is a linker that does not contain any biologically or chemically labile bond and an active catabolite is released by the complete degradation of the antibody. The released catabolite will contain the amino acid from the antibody to which the linker-payload was conjugated. Catabolites from non-cleavable linkers do not cross membranes passively and thus do not distribute within a tissue. The two most common non-cleavable linkers that are used are maleimidocaproyl (Mc) and succinimidyl trans-4-(maleimidylmethyl)cyclohexane-1-carboxylate (SMCC). In general, a non-cleavable linker is better tolerated but less efficacious.31
The most popular linker is the protease cleavable linker that contains a valine-citrulline-para-aminobenzyl-carbamate moiety (vc-PABC).32 This is a traceless linker that allows the release of amine containing cytotoxins. Many di-, tri-, and tetra-peptide sequences are cleaved by proteases and changing the sequence can facilitate the synthesis of the linker-payload and improve the properties of the ADC construct. There are also traceless cleavable linkers that get cleaved by glucuronidases that offer higher water solubility.33 The advantages of cleavable linkers are that they have good plasma stability and robust activity in a variety of cell lines and preclinical models.34
Another means of releasing cytotoxin is to use the acidic environment found in the tumor microenvironment and in the lysosome. Hydrazones and carbonates are two commonly used motifs for pH-sensitive linkers. These acid labile linkers shed cytotoxins in circulation but are still powerful linker motifs.11 Finally, the last type of cleavable linker discussed will be the one containing reducible bonds. These are usually identified by their disulfide bond which breaks in half in the presence of cysteine or glutathione. The advantages of disulfide linkers are that the kinetics of release can be controlled by steric bulk.35
Figure 8: Top Disclosed ADC Linkers3
Non-specific payload release is a common problem encountered with the usage of existing linkers. The resulting off-target toxicity becomes a prime cause for limiting the therapeutic window.17 ADC stability and safety is primarily affected by factors such as the linker length, hydrophilicity, site of conjugation, conjugation method and steric hindrance around the site of the linker.36 While designing an ADC it could be considered that if, for example, the tumor has consistent expression throughout the tissue then one could consider non-cleavable linkers to lower toxicity. If there is heterogeneous expression, then a cleavable linker generating a membrane permeable catabolite (with bystander activity) would be advantageous. But if there is low expression, then a potent cytotoxin will be required. With this information in hand, one can start testing the linker-payload that has the best chance of success and begin refining the ADC from the data generated.
Conjugation Technologies
DAR is a critical quality parameter which influences the overall efficacy, pharmacokinetics, and safety profile of an ADC molecule. This ratio is typically determined by the conjugation method employed during the development stage. The DAR is measured by a variety of analytical techniques, which should give similar results but almost never the same number.37 Hence the usage of two different methods to determine the DAR is highly recommended. As the field evolves, finding orthogonal methods for DAR determination is becoming more routine.38 The distribution of stochastic conjugations is usually referred to as heterogeneous, that is a mixture of populations (DAR 0 – 8) is obtained to give an average DAR (e.g., DAR 4), or homogeneous when the population is mostly one species (e.g., mostly DAR 2).39
IgG molecules generally possess multiple intrinsic sites that can be engineered by introducing electrophilic handles to create reactive sites for bioconjugation. . Non-specific or stochastic conjugation methods utilize natural nucleophilic amino acids found on the antibody, particularly lysine and cysteine residues and do not require antibody engineering.
There are 80 lysine residues in an IgG molecule, among which 20 are located in highly solvent-accessible positions.40 Lysine-based conjugations are carried out by mixing the mAb with an activated ester. This generally results in a DAR distribution between 0 and 9 with an average DAR of 3.5. In contrast, cysteine residues are less abundant but are uniformly distributed throughout the antibody structure thus reducing heterogeneity as compared to lysine conjugation. There are 16 pairs of cysteines, which comprise of 12 intrachain disulfide bonds and 4 interchain bonds. Cysteine conjugation generally involves partial reduction of these 4 interchain bonds to form reactive cysteine thiol groups. These thiols are then available to react with thiol-specific maleimide linkers. The DAR is typically controlled by the amount of reducing agent used at the reduction stage. The standard conjugation using cysteine aims for a DAR around 4 with a DAR distribution between 0-8 for IgG1 antibodies. Currently, most ADCs employ cysteine conjugation for the attachment of the linker-payloads.39,41
Figure 9: DAR Distribution between Heterogeneous (Stochastic) and Homogeneous Conjugations8
This stochastic approach often leads to the generation of a heterogeneous population of different species with a widely distributed DAR. A low DAR could present significant challenges like reduced efficacy, higher dosage requirements and suboptimal tumor penetration. On the other hand, an ADC with a higher DAR is more susceptible to aggregation, rapid systemic clearance and toxicity concerns.42 Since each of these generated subpopulations have different PK and efficacy profiles it could be hard to predict the effect of all the different species during clinical trials. A small population of such species could be generating most of the toxicity observed, due to extensive antibody modification, which may also cause structural changes affecting the biological function.43
To address these challenges, several site-specific conjugation technologies have been developed. These strategies can create a more homogeneous ADC population with improved plasma stability, heightened tumor uptake, and enhanced binding efficiency.43 The case of homogeneous ADCs into the clinic involved the modification of each interchain disulfide bonds (DAR8), enabling precise and site-specific conjugation, as demonstrated by trastuzumab deruxtecan (Enhertu®). This advancement allowed for more consistent DARs and improved therapeutic outcomes. In the past few years, numerous site-specific conjugation technologies have been developed. Table 5 provides an overview of commonly employed strategies in developing ADC constructs with improved homogeneity and therapeutic index.
Table 5. List of ADC Conjugation Technologies
Conjugation Methods/ Platform | Developed by | DAR | Description/ Features | Example(s) of ADCs using the technology | References |
STOCHASTIC CONJUGATION | |||||
Lysine sites | Heterogeneous ADC product | Activated ester groups undergo a stable covalent bond formation with primary amines found on the side chains of exposed lysine residues. | Marketed: Gemtuzumab ozogamicin (Mylotarg), Trastuzumab emtansine (Kadcyla), Inotuzumab ozogamicin (Besponsa), Mirvextuximab soravtansine (Elahere) | nature.com | |
Cysteine sites | Heterogeneous ADC product | This approach utilizes cysteine residues generated through partial reduction of interchain disulfide bonds. Subsequent thiol-maleimide coupling involves a linker containing a maleimide group. This group reacts with the thiol (SH) groups of up to eight reduced cysteines in the IgG1 hinge region, typically engaged in four interchain disulfide bridges. | Marketed: Brentuximab vedotin (Adcetris), Polatuzumab vedotin (Polivy), Enfortumab vedotin (Padcev), Tisotumab vedotin (Tivdak), Disitamab vedotin (Aidexi), Loncastuximab tesirine (Zynlonta) | nature.com | |
SITE-SPECIFIC CONJUGATION | |||||
Engineered reactive cysteines/ Cysteine conjugation | |||||
THIOMAB™ | Genentech | 2 | The technology strategically introduces cysteine (Cys) residues at specific positions within the heavy or light chains of antibodies. Drugs are selectively conjugated to the engineered cysteines, preserving the structural integrity of the disulfide bonds within the antibody. | Phase1/2: HDP-101, Phase 1: DMUC4064A Preclinical: ITC-6102RO | pubmed.ncbi.nlm.nih.gov |
Selenomab™ | Scripps Research Institute | Selenomabs represent engineered mAbs with strategically incorporated selenocysteine residues through translational processes. The distinctive reactivity of selenocysteine's selenol group allows for precise drug conjugation at specific sites. Their high reactivity facilitates rapid, efficient, and single-step reactions, closely mirroring physiological conditions. | pubs.rsc.org | ||
Actibody | Kyowa Hakko Kirin Co., Ltd. | The Actibody (Active thiol antibody) has an LC-Q124C mutation positioned at a less exposed site. This occurs by substituting cysteine at Gln124 in the light chain of the targeted antibody. | repository.kulib.kyoto-u.ac | ||
CYSMAB Technology | ImmunoGen | 2 | ADCs site specifically conjugated at HC-C442 | Phase 1/2: Pivekimab Sunirine | pubs.acs.org |
Full Reduction of interchain disulfides | N/A | 8 | In the modification process of IgG1 antibodies, naturally occurring cysteine residues become accessible by reducing the four interchain disulfide bonds. This reduction reveals up to eight reactive thiol residues, and subsequently, the antibodies are conjugated with eight payloads, each attaching to one of the available cysteines. Reduction of interchain disulfides reveals thiol residues, reactive towards soft electrophilic reagents. Full reduction and complete reaction of all eight reactive cysteines results in DAR 8 conjugates | Marketed: Sacituzumab govitecan (Trodelvy), Trastuzumab deruxtecan (Enhertu) | pubs.rsc.org |
Flexible Antibody Conjugation Technology (FACT) Platform | Pyxis Oncology (in-licensed from Pfizer) | Technology involves the site-specific conjugation of the linker-payload to engineered cysteine residues, enhancing anti-tumor activity, safety, and tolerability. | Phase 1: PYX-201 | adcreview.com | |
ByonShieLD® | Byondis | Utilizing orthogonal cysteine activation and conjugation technology, this method produces consistent ByonZine® ADCs. The process involves shielding the hydrophobic payload, resulting in ADCs characterized by a superior therapeutic index and exceptional manufacturability. | Phase 1: BYON3521 | adcreview.com | |
RESPECT-L®(REsidue SPEcific Conjugation Technology) | Eisai | 2 | Rabbit antibodies exhibit a unique intrachain disulfide bond between the Vκ and Cκ domains. Preserving the Vκ cysteine (Cys80) in the humanization process results in an unpaired cysteine, which shows high conjugation efficiency. | adcreview.com | |
WuXiDARx™ | WuXi Biologics | 2,4,6 | In this approach, a metal ion blocker is introduced into the antibody solution during the reduction phase, facilitating the targeted reduction of disulfide bonds. Thiol-reactive linker-payloads are then applied for conjugation with sulfohydryls (-SH), followed by quenching and the restoration of the blocked hinge region through oxidative recovery. In the WuXiDAR2 and WuXiDAR6 platforms, native antibodies undergo a proprietary process without intermediate purification steps. This process results in the reduction of 1 or 3 disulfide bonds, yielding 2 or 6 thiol groups, respectively. Thiol-reactive linker-payloads are subsequently introduced for conjugation. This technology offers a narrow DAR distribution (composition of the desired DAR ≥ 70%) | wuxibiologics.com | |
PermaLink™ | Iksuda (previously Glythera) | This approach can be used for cysteine-based heterogeneous conjugation with wild-type antibodies and homogeneous conjugation with antibodies featuring engineered cysteines. The vinyl segment of PermaLink, derived from its vinyl-pyridine-based chemistry, effectively interacts with the thiol group present in the amino acid cysteine. | Preclinical: IKS01 | iksuda.com | |
P5 Conjugation | Tubulis GmbH | 8 | This approach involves cysteine-selective chemistry and employs a process that utilizes disulfide bond reduction and Staudinger-induced Michael addition. | ashpublications.org | |
Unnatural amino acids (UAA) engineering | |||||
EuCODE™ | Ambrx | This process involves the integration of non-natural amino acids into heterologous proteins. It is achieved by incorporating three non-natural components into the expression system including, non-natural amino acid, supplemented into the growth medium; orthogonal aminoacyl-tRNA synthetases (aaRS); and an orthogonal tRNA. | Phase 3: ARX788, ARX517 | patentimages.storage.googleapis.com | |
Xpress CF+™ | Sutro Biopharma | This cell-free protein synthesis system generates antibodies incorporating non-natural amino acids. This capability allows for precise conjugation of uniform antibody drug conjugates (ADCs) through click chemistry at specific sites. | Phase 2: Luveltamab tazevibulin | pubmed.ncbi.nlm.nih.gov | |
SMARTag® Technology | Redwood Bioscience (Subsidary of Catalent) | 0 to 8 | This approach involves incorporating formylglycine (fGly), a non-natural amino acid, into the protein sequence. A tagged construct is created by inserting a short consensus sequence (CxPxR) at the desired location. Coexpressing this construct with the formylglycine-generating enzyme (FGE) in cells leads to the conversion of cysteine within the tag into fGly during translation, resulting in an antibody with two aldehyde tags per molecule. The aldehyde tags serve as chemical handles for bioorthogonal conjugation. Using the Hydrazino-iso-Pictet-Spengler (HIPS) ligation, the cytotoxin payload is connected to fGly, forming a stable, covalent C−C bond between the payload and the antibody. | Phase 1: TRPH-222 | pubmed.ncbi.nlm.nih.gov |
Enzyme Assisted Ligation | |||||
BTG (Bacterial transglutamination) | MI Abs & Innate Pharma | 2 or 4 | The utilization of Bacterial transglutaminase (BTG) enables the attachment of payload-linkers at multiple positions in antibodies through the incorporation of an LLQGA tag. | Preclinical: Immunitas Therapeutics anti-CLEC2D-TLR9-ISAC | ncbi.nlm.nih.gov |
Tub-Tag® | Tubulis | 2or 4 | Tubulin tyrosine ligase (TTL), and enzyme involved in intracellular regulation of microtubule stability, recognizes a 14-amino acid motif at the C-terminus of alpha-tubulin. When fused to an antibody, this recognition motif (Tub-tag) enables TTL to attach unnatural tyrosine derivatives that carry reactive groups, facilitating chemoselective conjugation. | Preclinical: TUB-010 | ncbi.nlm.nih.gov |
SMAC™ | NBE-Therapeutics | This method conjugates a pentaglycine-modified toxin to the C-termini of LPETG-tagged antibody heavy and light chains using sortase-mediated antibody conjugation. | Phase 1/2: SOT102, NBE-002 | ncbi.nlm.nih.gov | |
iGDC™ (Intelligent glycosyltransferase dependent conjugation) | GeneQuantum | This method involves employing immobilized engineered glycosyltransferase to achieve accurate and effective coupling of payloads to designated locations on antibodies. | Preclinical: BioMap-GeneQuantum ADC, GeneQuantum dpADC (iLDC™ and iGDC™) | genequantum.com | |
iLDC™ (Intelligent Ligase Dependent Conjugation) | GeneQuantum | 2 | This approach uses immobilized engineered transpeptidase for the accurate and efficient conjugation of payloads to specific antibody sites. | Phase 1/2: GQ1001 | genequantum.com |
RESPECT-H®(REsidue SPEcific Conjugation Technology) | Eisai | This C-terminal lysine-specific linkage technique, utilizes the transglutaminase enzyme to catalyze the formation of a durable isopeptide bond. This bond forms between the γ-carboxyamide group (acyl donor) of a glutamine and the ε-amino group (acyl acceptor) of a lysine. | Phase 2: BB-1701 | adcreview.com | |
Peptide Asparaginyl Ligase (PAL) one-pot conjugation | Singzyme & Lonza | 2, 4. 6, 8 | This approach facilitates the site-specific attachment of payloads with peptidic linkers to antibody, using highly efficient peptide asparaginyl ligases (PAL). The mAbs undergo conjugation at C-termini of both their L and H chains to produce a DAR 4 bioconjugate. DAR 2 conjugates can be produced by labeling either the L or H chain only and DARs higher than 4 via dual N- and C-conjugation or by using a higher payload to linker ratio. | adcreview.com | |
ConjuAll™ | LegoChem Biosciences | 2 | This approach utilizes novel linker chemistry combined with site-specific enzymatic conjugation | Phase 3: FS-1502 | adcreview.com |
Glycan remodelling & glycoconjugation | |||||
GlycoConnect™ | Synaffix | This approach leverages the conserved N-glycosylation site to produce site-specific ADCs through enzymatic remodeling and click chemistry without the need for metal catalysts. The existing antibody glycan is replaced with a therapeutic payload. | Phase 1/2: MRG004a | pubmed.ncbi.nlm.nih.gov | |
GlycOBI™ | OBI Pharma | DAR4, DAR8 or DARX | This method incorporates OBI's exclusive enzymatic technology, EndoSyme OBI™ and conjugates the hydrophilic linker-payloadto the glycan site naturally present in the Fc region of the antibody. | Preclinical: OBI Pharma BsADC | obipharma.com |
GlyCLICK | Genovis AB | 2 | The process involves Fc-glycan remodeling achieved through the complete deglycosylation of the antibody. This method of site-specific conjugation is based on click-chemistry and is carried out through a two-step enzymatic procedure, transforming Fc-glycans on IgG monoclonal antibodies into two anchor points for conjugation with any alkyne-containing payload. | Preclinical: Genovis Glykos ADC | pubmed.ncbi.nlm.nih.gov |
Short Peptide Tags | |||||
NexMab™ | Alteogen | This method employs motifs containing ligand-protected cysteines. It involves introducing peptide motifs with cysteine residues at the C-terminus of the heavy chain of an antibody. | Phase 1: ALT-P7 | sciencedirect.com | |
AbClick® Pro & AbClick® Standard | AbTis | 2,4,6,8 | This click-chemistry based approach relies on the proximity effect to conjugate payloads to lysine residues on the Fc site of antibodies. Cyclic peptides reversibly bind to the IgG Fc domain and the payload is attached. AbClick® Pro, equipped with a binding site for FcRN, leads to a comparatively prolonged half-life, while AbClick® Standard, lacking the FcRN binding site, exhibits a relatively shorter half-life. | Preclinical: AbTis and WuXi XDC ADC, AbTis CD22 ADC | abtis.co.kr |
pClick Technology | Rice University & Peking University | This approach is based on the proximity-induced reactivity between an affinity peptide cross-linker and a nearby antibody lysine residue. Solid-phase peptide synthesis is employed to incorporate the FPheK moiety at a designated site within the affinity peptide. When the affinity peptide binds to the antibody, the presence of FPheK facilitates covalent attachment to a nearby lysine residue on the antibody through proximity-induced reactivity. | ncbi.nlm.nih.gov | ||
Native cysteine rebridging | |||||
McSAF Inside® | McSAF and Lonza | 2, 4 | This is a cysteines rebridging technology platform conjugating the payload to the target protein at the native interchain disulfides. | Preclinical: ADCITMER®, McSAF 01 | lonza.com |
ThioBridge™ | PolyTherics/ Abzena | 4 | Following the reduction of an intra-chain bond, two free cysteine thiols are generated. These can be specifically conjugated at the site with a bis-thiol alkylating reagent (ThioBridge), to which the payload is already attached via a releasable/nonreleasable linker. The ThioBridge disulfide-bridging reagent undergoes bis-alkylation to connect to both cysteine thiols derived from the reduced disulfide. | Phase 1: Oba01, MBRC-101; Discontinued : OBI-999 | genengnews.com |
Fc affinity mediated | |||||
AJICAP® site specific conjugation | Ajinomoto | 2 | This linker structural tuning approach enables site-specific modification of native IgGs at the novel conjugation site (Lys288) | Preclinical: AJICAP-ADCs | ajibio-pharma.ajinomoto.com |
Modification of N/ C terminal of Antibody | |||||
N terminal serine conjugation | ImmunoGen | Engineered serine residues can be strategically placed at four distinct N-terminal positions on the antibody. Modifying the N-terminus ensures that the attached payload is positioned far from the antibody's target binding sites in the variable region CDRs. | aacrjournals.org | ||
N-terminal glutamate conjugation | N/A | N-terminal glutamate is selectively modified with aldehyde functionalised payloads | pubs.rsc.org | ||
N-terminal cysteine conjugation | N/A | N-terminal cysteine is selectively modified with aldehyde functionalised payloads | pubs.rsc.org | ||
π-clamp tag mediated | N/A | π-clamp peptide sequence selectively reacts with perfluoroaromatic probe | pubs.rsc.org | ||
DBCO tag mediated | N/A | DBCO (cysteine containing peptide) tagged antibody selectively reacts with DBCO reagents via. the thiol-yne reaction | pubs.rsc.org | ||
CD38 tag mediated | N/A | CD38 tag reacts with covalent inhibitor tagged payload, forming a stable arabinosyl ester | pubs.rsc.org | ||
NTERM Conjugation | ABL Bio | 3.2 (weighted average) | In this approach, payloads were linked to the N-terminal of an antibody by creating amine bonds through reductive alkylation reactions. | Preclinical: TSD101 | ncbi.nlm.nih.gov |
Disulfide bridging | |||||
C-Lock™ | Sorrento Therapeutics (Previously Concortis Biosystems, Corp.) | This approach employs an innovative linker chemistry to re-connect the reduced disulfide bonds between the H and L chains of the antibody, simultaneously enabling the incorporation of a drug into each reconnected disulfide bond. | Phase 1/2: STI-6129 | aacrjournals.org | |
Linker controlled conjugation technology | |||||
K-Lock™ | Sorrento Therapeutics (Previously Concortis Biosystems, Corp.) | This technology is highly selective on one or two specific sites among the 80-90 lysine side chains present on an antibody. The generated ADCs exhibit reduced regioisomers and a lower DAR. | Phase 3: Trastuzumab botidotin | aacrjournals.org | |
Others | |||||
MuSC™(Multifunctional Site-specific Conjugation) | Adcoris | 2,4,6,8,10 | Enables the development of typical ADC and new-structure ADC, i.e., dual payload ADC and bispecific ADC. Offers CMC advantage, multifunctionality, low immunogenecity risk and pervasiveness | Preclinical: ADC2154, ADC2192 | adcoris.com.cn |
Novel Payload Strategies
To mitigate the issues of toxicity and reduced half-life it would be beneficial if we could keep the DAR below 4 while maintaining ADC efficacy. For this reason, selecting an appropriate payload for a specific disease indication and using it at the optimal concentration based on its IC50 value is crucial. Cytotoxic compounds have different permeabilities, hydrophobicities, potencies and mechanisms of action. Payloads have diversified over years of research and novel strategies like topoisomerase II inhibitors, transcription inhibitors, protein synthesis inhibitors, PROTACs, and immunomodulators have been developed.A diverse array of payloads including small molecules, protein toxins, radionuclides, cytolytic immunomodulatory proteins, biologically active peptides and enzymes are under preclinical and clinical investigation.20 Table 6 summarizes both payloads that are in use or under investigation in ADC development.
Figure 10: ADC Payloads by Mechanism of Action3 (left), and IC50/ potency of various payload types , (right)44,45
Table 6: Conventional and novel ADC Payloads3
Payload Class | Payloads | Examples |
Tubulin inhibitors | Auristatin | MMAE, MMAF, Duostatin5, Duostatin5.2, SHR152852, MMAD, LP2, PF-06380101/ Aur0101, Auristatin F-HPA, Auristatin W analog, F55443, MMAU, ZD02044 |
Maytansine | DM4, DM1, DM21, M24 | |
Tubulysin | AZ13599185, Tubulysin A, Tub114, Tub201, Tub255, Tub196 | |
Others | Cytolysin, Eribulin, KSP inhibitor, PM050489, Cryptophycin, Paclitaxel, Docetaxel, DIACC2010, TAM470, AP052, Utidelone | |
DNA Damaging Agents | Calicheamicin | -- |
Duocarmycin | DUBA, NMS-P528, MED-A/DNAMGBA toxin | |
Indolino-benzodiazepine dimer (IGN) | DGN549, DGN462, IGN-P1 | |
Pyrrolobenzodiazepine (PBD) | SG3199, SG3552, SG2000, D211, I-BiPs, SG2057, SGD1882, SC-DR003, SG3249, SG3376 | |
Pyridinobenzodiazepine (PDD) | FGX2-62, FGX20-75 | |
Others | Lidamycin, Azonafide, Thienoindole, Temozolomide, Cyclopropylpyrroloindole (CPI), dHBD, AxcynDOT™ (Trabectedin) | |
Topoisomerase inhibitors | Topoisomerase I inhibitors | SN-38, CPT-113, Exatecan, DXd/ DX8951, Camptothecin, ATI020, LMP517 (dual action), AZ14170132, Ed-04, Belotecan, Tubutecan, YL0010014, AMDCPT, BCPT02, D2102, Dxh, KLG10023, LD2, P1003, P1021, PBX-7, SHR9265, VIP716, YL0014, ZD06519 |
Topoisomerase II inhibitors | Doxorubicin, PNU-159682, Anthracycline | |
Immunomodulators | Agonists | STING agonist, TLR7 Agonist, TLR 7/8 agonist, TLR8 agonist, TLR9 agonist, TAK676, CRD5500, IMSA172, JAB-27670, Resiquimod (R848), SZU-101, Tacrolimus (FK506) |
Other Payload Classes | RNA polymerase II inhibitor | Amanitin, Triptolide, Thailanstain |
Degradation | SMol006, Lenalinomide, GNE-987, PROTAC, PRT3789 (SMARCA2), GSPT1 degrader, BRD4 degrader, RIPK2 degrader | |
Other Novel Payloads (Modulators) | siRNA, ASO, Bcl-xL inhibitor, Steroids, dmDNA31, Urease, Glucocorticoids, Na; K-ATPase inhibitor, Phosphonate, NMT inhibitor, TGFβR antagonist, CEN-106, CEN371, CLYP-71 (Lytic peptide), CpG ODNs, EBET-1055, Glucagon-like peptide-1 analogues, Granzyme B, MYX2339, N-linked glycosylation inhbitor-1, Saporin, siDUX4.6 |
Novel ADCs
Figure 11: Novel ADCs
i. Immunostimulatory Antibody Conjugates (ISACs)46 :
These conjugates are basically engineered mAbs linked with payloads that act as pattern recognition receptor (PRR) agonists. They work by enhancing the immune responses within the tumor microenvironment (TME) and further stimulate the adaptive immune system. Through the induction of pro-inflammatory cytokines and chemokines, they appear to be promising as monotherapies or in combination therapies and are currently in preclinical stages and early-phase clinical trials. .
ii. Degrader Antibody Conjugates (DACs):
Degrader-Antibody Conjugates (DACs) combine the catalytic activity of proteolysis targeting chimera (PROTAC) payloads with the specificity of antibodies,47 while overcoming the limitations of both ADCs and TPDs. DACs can recognize specific antigens and deliver degrader molecules to target tumors and tissues. These molecules have the potential to reduce toxicity associated with cytotoxic payloads while increasing the specificity of traditional degraders by linking them to highly specific mAbs.48
Several DACs are currently being studied and have demonstrated superior in vitro and in vivo activity against target tumor cells. Using the BT474 xenograft model, the effect of ORM-5029 has reported superior single-dose activity as compared to Kadcyla® and similar to that of Enhertu®. ORM-5029 and ORM-6151, developed to selectively deliver catalytic GSPT1 protein degraders to HER-2 and SIGLEC3-expressing tumor cells respectively, are currently in Phase I clinical trials.
Table 7: List of Preclinical and Clinical Degrader-Antibody Conjugates3
Drug Names | Highest Phase of Development | Drug Targets | Linker | Payload | Disease Indication |
ORM-5029 | 1 | GSPT1; HER-2 | Valine-Citrulline | SMol006 | Advanced Breast Cancer |
ORM-6151 | 1 | GSPT1; SIGLEC3 | β-Glucuronide | SMol006 | Acute Myelogenous/Myeloid Leukemia (AML); Acute Myeloid Leukemia; Myelodysplastic Syndrome |
84-EBET | Preclinical | BET proteins; CEACAM6 | GGFG (Glycine-Glycine-Phenylalanine-Glycine) | EBET-1593 | Pancreatic Cancer; Pancreatic Ductal Adenocarcinoma (PDAC) |
AnDC-0001 | Preclinical | Undisclosed | Undisclosed | Undisclosed | Cancer Indications |
AnDC-0002 | Preclinical | Undisclosed | Undisclosed | Undisclosed | Cancer Indications |
AnDC-0003 | Preclinical | GSPT1; Undisclosed (Antibody target) | Undisclosed | Undisclosed | Solid Tumors |
Bioloomics Antibody Degrader Conjugates | Preclinical | Undisclosed | Undisclosed | Undisclosed | Cancer Indications |
Debiopharm Ubix Antibody Degraducer® Conjugates | Preclinical | Undisclosed | Undisclosed | Undisclosed | Cancer Indications |
EBET-1055 | Preclinical | BET proteins; CEACAM6 | Undisclosed | EBET-1055 | Pancreatic Cancer; Pancreatic Ductal Adenocarcinoma (PDAC) |
FD-004 | Preclinical | HER-2 | Undisclosed | Undisclosed | Cancer Indications |
FD-005 | Preclinical | SIGLEC3 | Undisclosed | Undisclosed | Cancer Indications |
Firefly Bio DACs | Preclinical | Undisclosed | Undisclosed | Undisclosed | Liquid Tumors; Solid Tumors |
Genentech ADC PROTACs | Preclinical | BRD4; Undisclosed (Antibody target) | Undisclosed | Undisclosed | Prostate Cancer |
GNE-987 + CLL1 Ab | Preclinical | BET proteins; CLL-1 | Undisclosed | GNE-987 | Cancer Indications; Non-Cancer Indications |
GSK RIPK2 Ab-PROTAC | Preclinical | RIPK2; Undisclosed | Valine-Citrulline | Undisclosed | Cancer Indications |
GSPT1-0001 | Preclinical | GSPT1; Undisclosed (Antibody target) | Undisclosed | Undisclosed | Cancer Indications; Non-Cancer Indications |
iProgen/UBC Antibody-PROTAC | Preclinical | Undisclosed | Undisclosed | Undisclosed | Undisclosed |
Kangpu Biopharmaceuticals DAC1 | Preclinical | Undisclosed | Undisclosed | Undisclosed | Solid Tumors |
Kangpu Biopharmaceuticals DAC2 | Preclinical | Undisclosed | Undisclosed | Undisclosed | Hematological Malignancies |
Kangpu Biopharmaceuticals DAC3 | Preclinical | Undisclosed | Undisclosed | Undisclosed | Autoimmune Disease |
Merck Degrader-Antibody Conjugate | Preclinical | Undisclosed | Undisclosed | Undisclosed | Cancer Indications; Non-Cancer Indications; Undisclosed |
Merck-C4 Therapeutics Degrader-Antibody Conjugate | Preclinical | Undisclosed | Undisclosed | Undisclosed | Cancer Indications |
ORM-1023 | Preclinical | GSPT1; Undisclosed (Antibody target) | Undisclosed | Undisclosed | Neuroendocrine Tumors (Solid Tumors); Small Cell Lung Cancer (SCLC) |
Prelude-AbCellera SMARCA2 ADC | Preclinical | SMARCA2 | Undisclosed | PRT3789 (SMARCA2) | Hematological Malignancies; Solid Tumors |
PROTAb-0001 | Preclinical | Undisclosed | Undisclosed | Undisclosed | Cancer Indications; Non-Cancer Indications |
Seagen-Nurix DAC | Preclinical | Undisclosed | Undisclosed | Undisclosed | Cancer Indications |
Vertex-Orum Therapeutics Degrader-Antibody Conjugate | Preclinical | Undisclosed | Undisclosed | Undisclosed | Cancer Indications; Non-Cancer Indications |
iii. Dual-Drug ADCs49:
Dual-Drug or Dual-Payload ADCs (dpADCs) incorporate two distinct payloads with complementary mechanisms of action, aiming to deliver a more potent cytotoxic response to cancer cells. These drugs are currently in preclinical development as summarized in Table 8.
Drug Name | Payload | Homogenous Conjugate |
Dual PNU-159682/ MMAF conjugation | MMAF; PNU-159682 | Yes |
Tra-DualFab double conjugate | Alexa488; Alexa568 | Yes |
ZPDC | Paclitaxel, Gemcitabine | Undisclosed |
GeneQuantum HER3 dual-payload ADC | Undisclosed (Topoisomerase I inhibitor; tyrosine kinase inhibitor) | Yes |
CrossBridge Bio Dual-payload ADC (CB-120) | Undisclosed | Yes |
Phrontline Biopharma Bispecific Dual Payload ADC (2by2 ADC) | Undisclosed | Undisclosed |
SMP-Dual | Undisclosed | Yes |
Tripartite Therapeutics Dual Payload ADC | Polarpeutic agonist | Yes |
Toxicity concerns and mechanisms
Despite being designed to enhance the targeted delivery of cytotoxic payloads to specific cancer cells, ADCs often encounter challenges related to toxicity. First-generation ADC data revealed that only a small fraction (~0.003 – 0.08%) of the injected dose reached the intended tumor cell leading to the distribution of a significant amount of cytotoxin to non-target tissues and subsequent adverse events.
The toxicity associated with ADCs can be broadly classified into on-target and off-target toxicity. On-target toxicity occurs when the ADC binds to the intended cell surface protein on healthy cells, leading to adverse effects (Figure 12A). Off-target toxicity involves non-specific endocytosis, binding of the ADC to Fc/C-type lectin receptors, or internalization of free payload by passive diffusion across the cell membrane (Figure 12B and 12C)52. The bystander toxicity effect is observed when cleavage of the payload from ADCs leads to the diffusion of free payload into neighboring healthy cells.53
While ADCs with the same class of payload-linkers share similar toxicity profiles, using the same ADC to treat different cancers may result in varied toxicities. Common adverse events associated in late-stage clinical and marketed ADCs outlined in Table 9, can vary in severity, with some reaching grade 3 or higher. Among commonly used payload classes, peripheral neutropenia or thrombocytopenia is reported as the most common toxicity, followed by peripheral neuropathy, hepatotoxicity, skin rash, ocular toxicity, and toxicity of the gastrointestinal tract.54
Various strategies have been explored recently to address these challenges and reduce ADC-associated toxicities. These strategies include modifying conjugation technology or payload-linker chemistry, making antibody modifications, adjusting dosage regimens, and implementing inverse targeting strategies.52
Figure 12: Mechanism of ADC Toxicity52
Table 9: Common adverse effects associated with different payload classes
Common adverse effects associated with different payload classes | ||||||
Payload Class | Payload | Approved ADCs | ADCs in phase III of clinical trials | Linker Type | Key Toxicities/ Adverse side effects | References |
Tubulin inhibitors | MMAE | Adcetris®, Polivy®, Padcev®, Tivdak®, Aidexi® | 9MW2821, CMG901, MRG003, Sigvotatugum vedotinum, TPX-4589, Trastuzumab envedotin, Telisotuzumab vedotin, Trastuzumab vedotin | Valine-Citrulline (Cleavable) | Neutropenia, neuropathy, anemia, skin toxicities | https://doi.org/10.3390/cancers15030713 |
MMAF | N/A | FS-1502, Belantamab mafodotin | mc (Non-cleavable) | Thrombocytopenia, ocular toxicity, hepatic toxicity | https://doi.org/10.3390/cancers15030713 | |
DM1 | Kadcyla®, Ujvira™ | N/A | SMCC (Non-cleavable) | Thrombocytopenia, hepatic toxicity | https://doi.org/10.3390/cancers15030713 | |
DM4 | Elahere® | N/A | s-SPDB or SPDB (Cleavable) | Neutropenia, anemia, neuropathy, ocular toxicity | https://doi.org/10.3390/cancers15030713 | |
Amberstatin269 | N/A | ARX788 | Oxime (Non-Cleavable) | Ocular toxicity, anemia, pneumonitis | https://doi.org/10.1016/j.xcrm.2022.100814 | |
Auristatin F-HPA | N/A | Upinitatug rilsodotin | Fleximer Polymer (Cleavable) | Fatigue, nausea, aspartate aminotransferase increase, thrombocytopenia, decreased appetite | https://doi.org/10.1016/j.ctrv.2022.102489 | |
DNA damaging agents | Calicheamicin | Mylotarg®, Besponsa® | N/A | AcButacyl hydrazone disulfide (Cleavable) | Neutropenia, thrombocytopenia, hepatic toxicity | https://doi.org/10.3390/cancers15030713 |
PBD | Zynlonta® | N/A | Valine-Alanine (Cleavable) | Neutropenia, anemia, thrombocytopenia, serosal effusion, nephron toxicity, skin toxicity | https://doi.org/10.3390/cancers15030713 | |
Duocarmycin | N/A | Trastuzumab duocarmazine | Valine-Citrulline (Cleavable) | Neutropenia, thrombocytopenia, serosal effusion | https://doi.org/10.3390/cancers15030713 | |
Topoisomerase I inhibitors | SN-38 | Trodelvy® | N/A | CL2A (Cleavable) | Neutropenia, gastrointestinal toxicity | https://doi.org/10.3390/cancers15030713 |
Deruxtecan | Enhertu® | Datopotamab deruxtecan, Patritumab deruxtecan, Ifinatamab deruxtecan, JSKN-003 | GGFG (Cleavable) | Neutropenia, gastrointestinal toxicity | https://doi.org/10.3390/cancers15030713 | |
Belotecan | N/A | Sacituzumab tirumotecan | CL2A (Cleavable) | Neutropenia, anemia, thrombocytopenia | https://doi.org/10.1179/joc.2010.22.3.197 | |
SHR9265 (Exatecan) | N/A | Trastuzumab rezetecan | Undisclosed (Cleavable) | Neutropenia, leukopenia, anemia, thrombocytopenia | https://doi.org/10.1158/1538-7445.AM2023-CT204 | |
MMAE | Adcetris®, Polivy®, Padcev®, Tivdak®, Aidexi® | 9MW2821, CMG901, MRG003, Sigvotatugum vedotinum, TPX-4589, Trastuzumab envedotin, Telisotuzumab vedotin, Trastuzumab vedotin | Valine-Citrulline (Cleavable) | Neutropenia, neuropathy, anemia, skin toxicities | https://doi.org/10.3390/cancers15030713 |
Clinical Aspects of Antibody-Drug Conjugates
Figure 13: ADC Development Stages (September 2024)3
Approved Antibody-drug conjugates
The first ADC to receive market approval, gemtuzumab ozagamicin, was introduced in 2001 by Pfizer, withdrawn in 2010, and re-introduced in 2017 along with inotuzumab ozogamicin. Brentuximab vedotin, the second ADC launched in 2011 by SeaGen Inc. (formerly Seattle Genetics, Inc. and now Pfizer) and Millenium Pharmaceuticals/ Takeda, achieved $750 million in sales in 2023(9 months).55 Trastuzumab deruxtecan, launched by Daiichi Sankyo and trastuzumab emtansine, launched by Roche, continue to enjoy blockbuster status with $2.566 billion and $2.2 billion57 respectively in sales, in 2023. Between 2019 and 2022, additional ADCs have received approval, bringing the total number of approved ADCs to 13, as summarized in Table 10.
Table 10 : Approved Antibody-drug conjugates
INN | Brand Name | Antibody | Linker | Payload | Conjugation | DAR | Molecular Target | Approved Disease Indication | Approval Year | Developer | Black Box Warning | Tumor Type | Half life | Clearance Rate | Mechanism of Action | Dosage |
Gemtuzumab ozogamicin | Mylotarg® | IgG4 κ (Humanized) | AcButacyl Hydrazone disulfide (Acid labile hydrazone Cleavable) | Calicheamicin (DNA Damage) | Lysine | 2-3 | SIGLEC3 | AML | 2000, 2017 (Withdrawn in 2010) | Pfizer | Hepatotoxicity | Hematologic | 1st dose: 62 h, 2nd dose: 90 h | 0.35 L/h | DNA damaging agent | 3 mg/m2 (Q3D) |
Brentuximab vedotin | Adcetris® | IgG1 (Chimeric) | Valine-Citrulline (Protease Cleavable) | MMAE (Microtubule Disruption) | Cysteine | 4.0 | CD30 | HL, sALCL | 2011 | Takeda; Pfizer | Progressive Multifocal Leukoencephalopathy (PML) | Hematologic | 4-6 days | 1.457 L/ day | Tubulin inhibitor | 1.8 mg/kg (Q3W) |
Trastuzumab emtansine | Kadcyla® | IgG1 (Humanized) | SMCC (Non-cleavable) | DM1 (Microtubule Disruption) | Lysine | 3.50 | HER-2 | HER2+ Breast Cancer | 2013 | Genentech, Inc. | Hepatotoxicity, Cardiac Toxicity, Embryo-Fetal Toxicity | Solid | 4 days | 0.68 L/ day | Tubulin inhibitor | 3.6 mg/kg (Q3W) |
Inotuzumab ozogamicin | Besponsa® | IgG4 (Humanized) | AcButacyl Hydrazone disulfide (Acid labile hydrazone Cleavable) | Calicheamicin (DNA Damage) | Lysine | 2-3 | SIGLEC2 | (R/R) ALL | 2017 | Pfizer | Hepatotoxicity, including Hepatic Venoocclusive Disease (VOD)and increased risk of posthematopoietic stem cell transplant (HSCT) nonrelapse mortality | Hematologic | 12.3 days | 0.0333 L/ hr | DNA damaging agent | 0.5-0.8 mg/m2 (Q1W3) |
Polatuzumab vedotin | Polivy® | IgG1 (Humanized) | Valine-Citrulline (Protease Cleavable) | MMAE (Microtubule Disruption) | Cysteine | 3.5 | CD79b | DLBCL | 2019 | Genentech, Inc | N/A | Hematologic | 12 days | 0.9 L/ day | Tubulin inhibitor | 1.8 mg/kg (Q3WX6) |
Enfortumab vedotin | Padcev® | IgG1 κ (Human) | Valine-Citrulline (Protease Cleavable) | MMAE (Microtubule Disruption) | Cysteine | 4.0 | Nectin-4 | mUC | 2019 | Astellas Pharma Inc.; Pfizer | N/A | Hematologic | 3.4 days | 0.10 L/ hr | Tubulin inhibitor | 1.25 mg/kg (Q1WX3) |
Trastuzumab deruxtecan | Enhertu® | IgG1 (Humanized) | GGFG (Protease Cleavable) | DXd (Topoisomerase Inhibitor) | Cysteine (Site Specifically Conjugated) | 8.0 RPC | HER-2 | HER2+ Breast Cancer, Gastric Cancer | 2019 | AstraZeneca; Daiichi Sankyo, Inc. | Interstitial Lung Disease and Embryo-Fetal Toxicity | Solid | 5.7 - 5.8 days | 0.42 L/ day | Topoisomerase I inhibitor | 5.4 mg/kg (Q3W) |
Sacituzumab govitecan | Trodelvy® | IgG1 (Humanized) | CL2A (pH Sensitive -Cleavable) | SN-38 (Topoisomerase inhibitor) | Cysteine (Site Specifically Conjugated) | 7.6 | TROP-2 | mTNBC, mUC | 2020 (Accelerated Approval); 2021 (Full FDA Approval) | Gilead Sciences | Neutropenia and Diarrhea | Solid | 16 hours | 0.002 L/hr/kg | Topoisomerase I inhibitor | 10 mg/kg (Q1WX2) |
Loncastuximab tesirine | Zynlonta® | IgG1 (Humanized) | Valine-Alanine (Protease Cleavable) | PBD (DNA Damage) | Cysteine | 2.3 ± 0.3 | CD19 | DLBCL | 2021 (Accelerated Approval) | ADC Therapeutics S.A. | N/A | Hematologic | 7.06-12.5 days | 0.5-0.64 L/day | DNA damaging agent | 0.15 mg/kg Q3WX2 0.075 mg/kg Q3W |
Tisotumab vedotin | Tivdak® | IgG1 (Human) | Valine-Citrulline (Protease Cleavable) | MMAE (Microtubule Disruption) | Cysteine | 4.0 | Tissue factor | Cervical Cancer | 2021 (Accelerated Approval); 2024 (Full FDA Approval) | Pfizer | Ocular Toxicity | Solid | 2.26-7.25 days | 1.54 (%CV: 28.8) L/day | Tubulin inhibitor | 2 mg/kg Q3W |
Trastuzumab emtansine | Ujvira™ | IgG1 (Humanized) | SMCC (Non-cleavable) | DM1 (Microtubule Disruption) | Lysine | HER-2 | HER2+ Breast Cancer | 2021 (Approved for use in India) | Zydus Cadila | N/A | Solid | N/A | N/A | Tubulin inhibitor | 3.6 mg/kg Q3W | |
Disitamab vedotin | Aidexi® | IgG1 (Humanized) | Valine-Citrulline (Protease Cleavable) | MMAE (Microtubule Disruption) | Cysteine | 4.0 | HER-2 | Gastric Cancer | 2021 (Approved for use in China) | RemeGen; Pfizer | N/A | Solid | N/A | N/A | Tubulin inhibitor | 2.5 mg/kg Q3W |
Mirvetuximab soravtansine | Elahere® | IgG1 (Chimeric) | SPDB (Glutathione Cleavable) | DM4 (Microtubule Disruption) | Lysine | 3.4 | Folate Receptor Alpha | FRα+ platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer | 2022 (Accelerated Approval); 2024 (Full FDA Approval) | AbbVie | Ocular Toxicity | Solid | 4.8 days | 18.9 mL/hour | Tubulin inhibitor | 6 mg/kg Q3W |
AML: Acute Myeloid Leukemia, HL: Hodgkin's Lymphoma, sALCL:Systemic Anaplastic Large Cell Lymphoma, (R/R) ALL: relapsed or refractory acute lymphoblastic leukemia, DLBCL: Diffuse Large B-Cell Lymphoma, mUC: Metastatic urothelial cancer, mTNBC: Metastatic Triple-Negative Breast Cancer |
Combination Trials
ADC in combination with chemotherapy, molecularly targeted agents, radiotherapy, immunotherapy and endocrine therapy, are being explored in preclinical and clinical studies. Combination therapies generally reduce the likelihood of drug resistance and two agents with different mechanisms of action can be used to achieve favorable treatment outcomes.59 ADC monotherapies may be insufficient to treat certain tumor types, hence there is growing interest in exploring combination therapies. These trials appear to be primarily focused on advancing their use into earlier lines of therapy or earlier stages of disease. As per recent data, around half of the ADC trials initiated each year are combination trials (i.e. 166 out of 333 ADC trials in 2023) So far, 816 ADC combination trials have been registered, the majority of which pair an ADC with an immune checkpoint inhibitor (ICM).3 Currently, four ADCs have had combination therapies approved by global regulatory authorities. Table 11 summarizes these approved ADC combination therapies.
Common adverse effects associated with different payload classes | ||||||
ADC | Payload used in ADC | Combination Drugs | Target | Approved Indication | First Approved Date | Therapy |
Brentuximab vedotin | MMAE | Doxorubicin, Vinblastin, Dacarbazine (AVD) | CD30 | HL | 3/20/2018 | Chemotherapy |
Brentuximab vedotin | MMAE | Cyclophosphamide, Doxorubicin, Prednisone (CHP) | CD30 | PTCL | 11/16/2018 | Chemotherapy |
Brentuximab vedotin | MMAE | Doxorubicin, Vincristine, Etoposide, Prednisone, Cyclophosphamide | CD30 | cHL | 11/10/2022 | Chemotherapy |
Gemtuzumab ozogamicin | Calicheamicin | Daunorubicin, Cytarabine | SIGLE3 | AML, APL | 4/23/2018 | Chemotherapy |
Polatuzumab vedotin | MMAE | Bendamustine, Rituximab (BR) | CD79b | DLBCL | 6/10/2019 | ICM |
Polatuzumab vedotin | MMAE | Rituximab, Cyclophosphamide, Doxorubicin, Prednisone (R-CHP) | CD79b | BLBCL, NOS, HGBL | 4/19/2023 | ICM |
Enfortumab vedotin | MMAE | Pembrolizumab (KEYTRUDA®) | Nectin-4 | mUC | 4/3/2023 | ICM |
ADCs in Clinical Development: Future scope
Among 1262 ADCs identified by the close of 2023, approximately 26% i.e. 331 ADCs – have advanced into clinical trials. Notably, a significant proportion, 63%, of these clinical candidates are actively undergoing investigation in trials. There has been a significant growth in ADCs transitioning to clinical development and showing an upward trend from 2022 onwards.3
INN | Payload | Linker | Drug Targets | Disease Indication | Highest Phase of Development | Homogeneous Conjugates |
9MW2821 | MMAE (Auristatin) | Valine-Citrulline | Nectin-4 | Adenocarcinoma | 3 | Y |
Anvatabart opadotin | Amberstatin269 (AS269) (MMAF) | Oxime | HER-2; Tubulin | Adenocarcinoma of the Gallbladder | 3 | Y |
AOC 1001 | Undisclosed | Undisclosed | DMPK; Tfr1 | Central Nervous System Disease | 3 | Undisclosed |
Belantamab mafodotin | MMAF (Auristatin) | mc | BCMA | ALK Positive Systematic Anaplastic Large T-Cell Lymphoma (ALCL, ALK+) | 3 | N |
BL-M07D1 | Ed-04 (Alkaloid Camptothecin) | Undisclosed | HER-2 | Advanced Gastrointestinal Tumors | 3 | Y |
BAT8001 | Maytansine | 3AA | HER-2 | Advanced Breast Cancer | 3 | N |
CMG901 | MMAE (Auristatin) | Valine-Citrulline | CLDN18.2 | Adenocarcinoma of the Stomach | 3 | Undisclosed |
CPO-301 | Undisclosed | Undisclosed | EGFR | Adenocarcinoma | 3 | Undisclosed |
Datopotamab deruxtecan | DXd/DX8951 (MAAA-1181a) (Exatecan) | GGFG (Glycine-Glycine-Phenylalanine-Glycine) | TROP-2 | Adenocarcinoma of the Lung | 3 | N |
DB-1303 | P1003 | GGFG (Glycine-Glycine-Phenylalanine-Glycine) | HER-2 | Advanced Breast Cancer | 3 | Undisclosed |
ESG-401 | SN-38 (Irinotecan (CPT-11)) | Undisclosed | TROP-2 | Advanced HER2-Negative Breast Cancer | 3 | Undisclosed |
FDA018 | SN-38 (Irinotecan (CPT-11)) | Undisclosed | TROP-2 | Advanced Solid Tumors | 3 | Undisclosed |
FS-1502 | MMAF (Auristatin) | β-Glucuronide | HER-2 | Advanced Breast Cancer | 3 | Y |
HS-20093 | HS-9265 (Exatecan) | GGFG (Glycine-Glycine-Phenylalanine-Glycine) | B7-H3 | Advanced Esophageal Squamous Cell Carcinoma | 3 | Undisclosed |
IBI-343 | Exatecan (Camptothecin) | Valine-Alanine | CLDN18.2 | Advanced Gastric Adenocarcinoma | 3 | Y |
Ifinatamab deruxtecan | DXd/DX8951 (MAAA-1181a) (Exatecan) | GGFG (Glycine-Glycine-Phenylalanine-Glycine) | B7-H3 | Adenocarcinoma | 3 | N |
Depatuxizumab mafodotin | MMAF (Auristatin) | mc | EGFR | Advanced Solid Tumors Cancer | 3 | N |
Izalontamab brengitecan | Ed-04 (Alkaloid Camptothecin) | Undisclosed | EGFR; HER-3 | Advanced Colorectal Cancer | 3 | Y |
Enfortumab vedotin | MMAE (Auristatin) | Valine-Citrulline | Nectin-4 | Adenocarcinoma | 3 | N |
JSKN-003 | DXd/DX8951 (MAAA-1181a) (Exatecan) | GGFG (Glycine-Glycine-Phenylalanine-Glycine) | HER-2 | Advanced Solid Malignancies | 3 | Y |
MRG003 | MMAE (Auristatin) | Valine-Citrulline | EGFR | Advanced Biliary Tract Cancer | 3 | Undisclosed |
Patritumab Deruxtecan | DXd/DX8951 (MAAA-1181a) (Exatecan) | GGFG (Glycine-Glycine-Phenylalanine-Glycine) | HER-3 | Acral Melanoma; Breast Cancer | 3 | Y |
Sacituzumab tirumotecan | KL610023 (Belotecan) | CL2A | TROP-2 | Advanced Bladder Cancer | 3 | Y |
SHR-A1921 | SHR9265 (Exatecan) | Undisclosed | TROP-2 | Advanced Breast Cancer | 3 | Undisclosed |
Sigvotatug vedotin | MMAE (Auristatin) | Valine-Citrulline | Integrin beta-6 | Advanced HER2-Negative Breast Cancer | 3 | N |
Tecotabart vedotin | MMAE (Auristatin) | Valine-Citrulline | CLDN18.2 | Advanced Biliary Tract Cancer | 3 | Undisclosed |
Telisotuzumab vedotin | MMAE (Auristatin) | Valine-Citrulline | c-MET | Advanced Non-Small Cell Lung Cancer (NSCLC) | 3 | N |
TQB2102 | Undisclosed | Undisclosed | HER-2 | Advanced Biliary Tract Cancer | 3 | Undisclosed |
Trastuzumab botidotin | Duostatin5 (MMAF) | Valine-Citrulline | HER-2 | Advanced Breast Cancer | 3 | Y |
Trastuzumab duocarmazine | DUocarmycin-hydroxyBenzamide Azaindole (DUBA) (Duocarmycin) | Valine-Citrulline | HER-2 | Adenoid Cystic Carcinoma | 3 | N |
Trastuzumab envedotin | MMAE (Auristatin) | Valine-Citrulline | HER-2 | Advanced Breast Cancer | 3 | Y |
Loncastuximab Tesirine | SG3199 (Pyrrolobenzodiazepine (PBD)) | Valine-Alanine | CD19 | Acquired Immunodeficiency Syndrome (AIDS) | 3 | N |
Trastuzumab rezetecan | SHR9265 (Exatecan) | Undisclosed | HER-2 | Advanced Adenocarcinoma of the Stomach | 3 | N |
Trastuzumab vedotin | MMAE (Auristatin) | Valine-Citrulline | HER-2 | Advanced Biliary Tract Cancer | 3 | N |
Upinitatug rilsodotin | Auristatin F-HPA (XMT-1267) (Auristatin) | Fleximer Polymer | NaPi2b | Adenocarcinoma of the Lung | 3 | N |
Mirvetuximab soravtansine | DM4 (Maytansine) | Sulfo-SPDB | Folate Receptor Alpha | Adenocarcinoma of the Lung | 3 | N |
Rovalpituzumab tesirine | SG3199 (Pyrrolobenzodiazepine (PBD)) | Valine-Alanine | DLL3 | Advanced Small Cell Lung Cancer (SCLC) | 3 | N |
TAA013 | DM1 (Maytansine) | SMCC | HER-2 | Advanced Breast Cancer | 3 | N |
Tisotumab vedotin | MMAE (Auristatin) | Valine-Citrulline | Tissue factor | Adenocarcinoma | 3 | N |
Tusamitamab ravtansine | DM4 (Maytansine) | SPDB | CEACAM5 | Adenocarcinoma; Advanced Colorectal Cancer | 3 | N |
Ujvira | DM1 (Maytansine) | SMCC | HER-2 | HER2 Positive Breast Cancer | 3 | N |
Vadastuximab talirine | SGD-1882 (Pyrrolobenzodiazepine (PBD)) | Valine-Alanine | SIGLEC3 | Acute Myelogenous/Myeloid Leukemia (AML) | 3 | Y |
Luveltamab tazevibulin | SC209 (Hemiasterlin) | Valine-Citrulline | Folate Receptor Alpha | Adenocarcinoma | 2/3 | Y |
Raludotatug deruxtecan | DXd/DX8951 (MAAA-1181a) (Exatecan) | GGFG (Glycine-Glycine-Phenylalanine-Glycine) | CDH6 | Advanced Renal Cell Carcinoma | 2/3 | Y |
Vobramitamab duocarmazine | DUocarmycin-hydroxyBenzamide Azaindole (DUBA) (Duocarmycin) | Valine-Citrulline | B7-H3 | Adenocarcinoma of the Prostate | 2/3 | N |
Zilovertamab Vedotin | MMAE (Auristatin) | Valine-Citrulline | ROR1 | Acute Lymphocytic Leukemia | 2/3 | N |
Adalimumab fosimdesonide | Steroid | BrAc-Gly-Glu | TNF-alpha | Crohn's Disease | 2 | N |
AGS16F | MMAF (Auristatin) | mc | ENPP3 | Advanced Kidney Cancer | 2 | N |
Cantuzumab ravtansine | DM4 (Maytansine) | SPDB | CanAg | Advanced Gastric Cancer | 2 | N |
CMB-401 | Calicheamicin | AcBut acyl hydrazone-disulfide | MUC-1 | Clear cell epithelial ovarian cancer | 2 | N |
Coltuximab ravtansine | DM4 (Maytansine) | SPDB | CD19 | Acute Lymphoblastic Leukemia (ALL) | 2 | N |
Denintuzumab mafodotin | MMAF (Auristatin) | mc | CD19 | Acute Lymphoblastic Leukemia (ALL) | 2 | N |
Glembatumumab vedotin | MMAE (Auristatin) | Valine-Citrulline | gpNMB | Advanced Breast Cancer | 2 | N |
Indusatumab vedotin | MMAE (Auristatin) | Valine-Citrulline | GCC | Adenocarcinoma of the Stomach | 2 | N |
Labetuzumab Govitecan | SN-38 (Irinotecan (CPT-11)) | CL2A | CEACAM5 | Colorectal adenocarcinoma | 2 | Y |
Ladiratuzumab vedotin | MMAE (Auristatin) | Valine-Citrulline | LIV-1 | Advanced Breast Cancer | 2 | N |
Lifastuzumab Vedotin | MMAE (Auristatin) | Valine-Citrulline | NaPi2b | Advanced Epithelial Ovarian Cancer | 2 | N |
Lorvotuzumab Mertansine | DM1 (Maytansine) | SPP | CD56 | Acute Lymphoblastic Leukemia (ALL) | 2 | N |
Naratuximab emtansine | DM1 (Maytansine) | SMCC | CD37 | B-cell Non Hodgkin Lymphoma | 2 | N |
ABBV-3373 | Glucocorticoids (GCs) (Steroid) | Alanine-Alanine | TNF-alpha | Rheumatoid Arthritis | 2 | Undisclosed |
PSMA ADC | MMAE (Auristatin) | Valine-Citrulline | PSMA | Castration Resistant Prostate Cancer | 2 | N |
Anetumab ravtansine | DM4 (Maytansine) | SPDB | Mesothelin (MSLN) | Adenocarcinoma of the Breast | 2 | N |
BB-1701 | Eribulin | Valine-Citrulline | HER-2 | Advanced Breast Cancer | 2 | Y |
Camidanlumab Tesirine | SG3199 (Pyrrolobenzodiazepine (PBD)) | Valine-Alanine | IL-2R Alpha | Acute Lymphoblastic Leukemia (ALL) | 2 | N |
SAR566658 | DM4 (Maytansine) | SPDB | CA6 | Advanced Triple Negative Breast Cancer (TNBC) | 2 | N |
SGN-15 | Doxorubicin (Anthracycline) | Hydrazone | Lewis Y antigen | Advanced Non-Small Cell Lung Cancer (NSCLC) | 2 | N |
Delpacibart braxlosiran | siDUX4.6 | MCC | DUX4; Tfr1 | Facioscapulohumeral muscular dystrophy (FSHD) | 2 | Undisclosed |
Delpacibart zotadirsen | Undisclosed | Undisclosed | DMD; Exon 44; Tfr1 | Duchenne Muscular Dystrophy (DMD) | 2 | Undisclosed |
DX126-262 | Tub114 (Tubulysin) | polyethylene glycol | HER-2 | Advanced Breast Cancer | 2 | Undisclosed |
Farletuzumab Ecteribulin | Eribulin | Valine-Citrulline | Folate Receptor Alpha | Adenocarcinoma of the Lung | 2 | N |
FDA022 | Undisclosed | Undisclosed | HER-2 | Advanced Breast Cancer | 2 | Undisclosed |
HS-20089 | Undisclosed | Undisclosed | B7-H4 | Advanced Solid Tumors | 2 | Undisclosed |
L-DOS47 | Urease | SIAB (N-succinimidyl [4-iodoacetyl] aminobenzoate) | CEACAM6 | Adenocarcinoma of the Lung | 2 | Undisclosed |
Maridebart cafraglutide | Glucagon-like peptide-1 analogues | Undisclosed | GIPR; GLP-1R | Adiposity/Obesity; Cardiovascular Diseases; Diabetes Mellitus | 2 | Undisclosed |
Mecbotamab vedotin | MMAE (Auristatin) | Valine-Citrulline | Axl | Advanced Solid Tumors | 2 | N |
Misitatug blivedotin | MMAE (Auristatin) | Valine-Citrulline | Mesothelin (MSLN) | Advanced Malignant Tumors | 2 | Undisclosed |
Ozuriftamab vedotin | MMAE (Auristatin) | Valine-Citrulline | ROR2 | Advanced Non-Small Cell Lung Cancer (NSCLC) | 2 | N |
Praluzatamab ravtansine | DM4 (Maytansine) | SPDB | CD166 | Advanced Solid Tumors | 2 | N |
RC108 | MMAE (Auristatin) | Undisclosed | c-MET | Adenoid Cystic Carcinoma | 2 | Undisclosed |
Trastuzumab imbotolimod | Undisclosed | Undisclosed | HER-2; TLR7/8 (Payload target) | Adenocarcinoma of the Breast | 2 | Undisclosed |
SHR-4602 | Undisclosed | Undisclosed | HER-2 | Advanced Solid Tumor Malignancy | 2 | Undisclosed |
SHR-A1904 | Undisclosed | Undisclosed | CLDN18.2 | Advanced Pancreatic Cancer | 2 | Undisclosed |
SHR-A2009 | Undisclosed | Undisclosed | HER-3 | Advanced Non-Small Cell Lung Cancer (NSCLC) | 2 | Undisclosed |
SHR-A2102 | Undisclosed | Undisclosed | Nectin-4 | Advanced Esophageal Squamous Cell Carcinoma | 2 | Undisclosed |
Telisotuzumab adizutecan | Camptothecin | Valine-Alanine | c-MET | Advanced Colorectal Cancer | 2 | Undisclosed |
Unspecified HER2 ADC | Undisclosed | Undisclosed | HER-2 | Breast Cancer | 2 | Undisclosed |
Unspecified TROP2 ADC | Undisclosed | Undisclosed | TROP-2 | Advanced Breast Cancer | 2 | Undisclosed |
YL201 | YL0010014 (Camptothecin) | TMALIN | B7-H3 | Advanced Solid Tumors | 2 | Undisclosed |
YL202 | YL0014 (Camptothecin) | TMALIN | HER-3 | Advanced Breast Cancer | 2 | Y |
Antibody-drug conjugates for non-oncological applications
While the majority of ADCs in development remain focused on oncology, the landscape is gradually expanding. Unlike in oncology, these ADCs utilize non-toxic payloads to modulate biological functions without affecting cell viability.62 The identification of highly specific targets and development of non-toxic payloads (anti-inflammatory, anti-infective or neuroprotective) specific to the disease indication is essential to minimize off-target effects. Additionally, their usage in chronic non-oncological indications may increase the risk of immunogenicity, requiring careful design. While its research for non-cancer indications is still in its early stages, ongoing preclinical and early-phase clinical trials hold promise. Applications in myotonic dystrophy, scleroderma, Duchenne muscular dystrophy, rheumatoid arthritis, amyloidosis, obesity and bacterial infections are currently being explored as summarized in Table 13.
Table 13: A list of ADCs that have been tested for indications other than oncology3
ADC | Disease Indication | Drug Target | Payload | Linker | Highest phase of development |
AOC-1001 | Myotonic dystrophy type 1 (DM1) | DMPK; Tfr1 | Undisclosed | Undisclosed | Ph 2 |
AOC-1020 | Facioscapulohumeral muscular dystrophy (FSHD) | Dux4; Tfr1 | siDUX4.6 | MCC | Ph 2 |
Brentuximab vedotin | Active diffuse cutaneous systemic sclerosis (Diffuse Scleroderma) | CD30 | MMAE | Val-Cit | Ph 2 |
Belantamab mafodotin | R/R AL Amyloidosis | BCMA | MMAF | Val-Cit | Ph 2 |
ABBV-3373 | Rheumatoid Arthritis | TNF-alpha | Steroid (Glucocorticoid) | Ala-Ala | Ph 2 |
AMG 133 | Adiposity/ Obesity; Type 2 Diabetes Mellitus; Hypertension | GIPR; GLP-1R | BiTE | Undisclosed | Ph 2 |
DYNE-251 | Duchenne Muscular Dystrophy (DMD) | Exon51; Tfr1 | Undisclosed | Undisclosed | Ph 1/2 |
Brentuximab vedotin | Systemic Sclerosis | CD30 | MMAE | Val-Cit | Ph 1/2 |
DYNE-101 | Myotonic dystrophy type 1 (DM1) | Undisclosed | DMPK; Tfr1 | Val-Cit | Ph 1/2 |
STI-6129 | R/R Systemic AL Amyloidosis | CD38 | Duostatin5.2 | Undisclosed | Ph 1/2 |
AOC 1044 | Duchenne Muscular Dystrophy (DMD) | DMD; Tfr1 | Undisclosed | Undisclosed | Ph 1/2 |
DSTA4637S | Bacteremia; Methicillin-sensitive Staphylococcus aureus; Methicillin-resistant Staphylococcus aureus | Staphylococcus aureus | dmDNA31 (Rifalog) | Val-Cit | Ph 1 |
Brentuximab vedotin | Graft vs. Host Disease (GVHD) | CD30 | MMAE | Val-Cit | Ph 1 |
Understanding the Challenges of Discontinued ADC Programs
Although the field of ADCs has had many successes and new approvals in the last few years, there are still many discontinued programs that provide important information. The most common reasons for discontinuation of ADCs include lack of sufficient efficacy at maximum tolerated dose (MTD), low tolerability, and safety reasons. Few others have also been discontinued due to pipeline reprioritization or due to the competitive landscape. Amongst the discontinued ADCs, most have used auristatin- and maytansinoid-based payloads, and in many cases, there may have been the wrong selection of drug-linker for the indication. Some antibodies targeting HER2+ cancers have not progressed in the clinic or did not show meaningful improvements to trastuzumab emtansine, but careful selection of new drug-linkers led to trastuzumab deruxtecan, a very promising new ADC. Table 14 displays targets and ADCs that have entered the clinic and have not proceeded. This knowledge along with careful analysis of the failures has the potential to inspire a new generation of ADCs.
Figure 14: Top payloads used in discontinued ADCs3 (left); and discontinued ADCs according to phase3 (right)
Name | Target | Indication | Drug-Linker | Payload | Last Phase | Reasons for Discontinuation | Discontinuation Year |
Adalimumab fosimdesonide | TNF-alpha | Crohn's Disease | BrAc-Gly-Glu | Steroid (Glucocorticoid receptor modulator) | Ph II | Benefit-risk profile does not sufficiently differentiate 154 from other available treatments | 2023 |
ADCT-502 | HER-2 | Solid tumors | Valine-Alanine | SG3199 (Pyrrolobenzodiazepine (PBD)) | Ph I | Lacks sufficient efficacy at the maximally tolerated dose level | 2018 |
AGS16F | ENPP3 | RCC | mc | MMAF (Auristatin) | Ph II | Did not meet its primary end point | 2019 |
AGS67E | CD37 | AML | Valine-Citrulline | MMAE (Auristatin) | Ph I | Undisclosed | 2018 |
AMG 172 | CD70 | RCC | MCC | DM1 (Maytansine) | Ph I | Undisclosed | 2016 |
AMG 595 | EGFRviii | Glioma | SMCC | DM1 (Maytansine) | Ph I | Undisclosed | 2018 |
ASG-5ME | SLC44A4 | Prostate Cancer | Valine-Citrulline | MMAE (Auristatin) | Ph I | Undisclosed | 2013 |
AVE9633 | SIGLEC3 | Acute Myelogenous/Myeloid Leukemia (AML) | SPDB | DM4 (Maytansine) | Ph I | Absence of evidence of clinical activity up to toxic doses | 2009 |
BAT8001 | HER-2 | Breast Cancer | 3AA | Maytansinoid (Maytansine) | Ph III | Did not achieve phase 3 clinical end points | 2021 |
BAT8003 | TROP-2 | Solid tumors | 3AA | Maytansine | Ph I | Considered development risk of drugs | 2021 |
BAY79-4620 | carbonic anhydrase IX (CAIX) | Solid tumors | Valine-Citrulline | MMAE (Auristatin) | Ph I | Safety reasons | 2011 |
BDC-2034 | CD66 | Breast Cancer | Undisclosed | TLR 7/8 agonist (TLR agonists) | Preclinical | Focus shifted to other promising programs | 2022 |
BIIB015 | Cripto | Solid tumors | SPDB | DM4 (Maytansine) | Ph I | Undisclosed | 2011 |
BioAtla-Pfizer ADC | Undisclosed | Cancer Indications | Undisclosed | Undisclosed | Preclinical | License and option agreement with Pfizer was terminated | 2020 |
Bivatuzumab Mertansine | CD44v6 | Squamous Cell Carcinoma | SPP | DM1 (Maytansine) | Ph I | Skin toxicity | 2005 |
Cantuzumab ravtansine | CanAg | Advanced Gastric Cancer | SPDB | DM4 (Maytansine) | Ph II | Slow pace of progress | 2009 |
CDX-014 | TIM-1 | RCC | Valine-Citrulline | MMAE (Auristatin) | Ph I | Costly to develop | 2018 |
CMB-401 | MUC-1 | Ovarian Cancer | AcBut acyl hydrazone-disulfide | Calicheamicin | Ph II | Dose-limiting toxicities | 2016 |
CMD-193 | Lewis Y antigen | Adenocarcinoma of the Lung | AcBut acyl hydrazone-disulfide | Calicheamicin | Ph I | Undisclosed | 2014 |
Cofetuzumab pelidotin | PTK7 | Advanced Non-Small Cell Lung Cancer (NSCLC) | Valine-Citrulline | PF-06380101 (Aur 101) (Auristatin) | Ph I | Undisclosed | 2023 |
Denintuzumab mafodotin | CD19 | ALL | mc | MMAF (Auristatin) | Ph II | Portfolio prioritization and restructuring initiatives | 2018 |
Depatuxizumab mafodotin | EGFR | AML | mc | MMAF (Auristatin) | Ph III | Lack of survival benefit | 2019 |
DHES0815A | HER-2 | Breast Cancer | Undisclosed | Pyrrolobenzodiazepine (PBD) | Ph I | Undisclosed | 2019 |
DS-6157 | GPR20 | Gastrointestinal Tumor | GGFG (Glycine-Glycine-Phenylalanine-Glycine) | DXd/DX8951 (MAAA-1181a) (Topoisomerase I inhibitor) | Ph I | No clear response in patients | 2021 |
Enapotamab vedotin | Axl | Solid tumors | Valine-Citrulline | MMAE (Auristatin) | Ph I/ II | Undisclosed | 2020 |
Glembatumumab vedotin | gpNMB | Breast Cancer | Valine-Citrulline | MMAE (Auristatin) | Ph II | Did not meet its primary end point | 2018 |
IMGC936 | ADAM9 | Advanced Solid Tumors | L-Ala-D-Ala-L-Ala | DM21 (Maytansine) | Ph I/ II | Phase 1 data failed to make the case for further development | 2024 |
IMGN388 | CD51 | NSCLC | SPDB | DM4 (Maytansine) | Ph I | Focus shifted to other resources | 2011 |
IMGN779 | CD33 | AML | Sulfo-SPDB | DGN462 (Indolino-benzodiazepine dimer (IGN)) | Ph I | Portfolio prioritization and restructuring initiatives | 2019 |
Indusatumab vedotin | GCC | ALL, AML | Valine-Citrulline | MMAE (Auristatin) | Ph II | Lack of efficacy | 2018 |
LOP628 | cKIT | AML | SMCC | DM1 (Maytansine) | Ph I | Undisclosed | 2016 |
Lorvotuzumab Mertansine | CD56 | ALL | SPP | DM1 (Maytansine) | Ph II | Lack of efficacy signal and safety concerns | 2013 |
Losatuxizumab vedotin | EGFR | Advanced Solid Tumors | Valine-Citrulline | MMAE (Auristatin) | Ph I | Safety reasons | 2018 |
MEDI4276 | HER-2 | Breast Cancer | mc-lysine | AZ13599185 (Tubulysin) | Ph I | Safety/ Efficacy reason | 2018 |
MEDI-547 | EphA2 | Bladder Cancer | mc | MMAF (Auristatin) | Ph I | Drug-related adverse events | 2012 |
MLN2704 | PSMA | Adenocarcinoma of the Prostate | SPP | DM1 (Maytansine) | Ph I/ II | Dose-limiting adverse effects | 2006 |
NJH395 | HER-2; TLR 7 (payload target) | Adenocarcinoma of the Small Intestine | Maleimide | TLR7 agonist (TLR agonists) | Ph I | No objective responses were observed in 18 treated patients | 2023 |
NN-ATAC | CD37 | Leukemia | Undisclosed | Amanitin | Preclinical | Undisclosed | 2019 |
OBI-999 | Globo H | Advanced Solid Tumors | Valine-Citrulline | MMAE (Auristatin) | Ph I/ II | Expected therapeutic potential not shown for the enrolled patients | 2023 |
Opelkibart elmanitin | cKIT | Acute Myeloid Leukemia | Undisclosed | Amanitin | Ph I | Grade 5 serious adverse event | 2023 |
PCA062 | P-Cadherin | Esophagus Cancer | SMCC | DM1 (Maytansine) | Ph I | Limited anti-tumor activity at the maximally tolerated dose level | 2022 |
PF-06263507 | 5T4 | Solid tumors | mc | MMAF (Auristatin) | Ph I | Portfolio prioritization and restructuring initiatives | 2015 |
PF-06647263 | EFNA4 | Solid tumors | AcBut acyl hydrazone-disulfide | Calicheamicin | Ph I | Change in sponsor prioritization | 2019 |
PF-06650808 | NOTCH3 | Solid tumors | Valine-Citrulline | PF-06380101 (Aur 101) (Auristatin) | Ph I | Undisclosed | 2016 |
PF-06664178 | TROP-2 | Solid tumors | Valine-Citrulline | PF-06380101 (Aur 101) (Auristatin) | Ph I | Business-related decision | 2016 |
PF-06688992 | GD3 | Melanoma | Undisclosed | Undisclosed | Ph I | Undisclosed | 2019 |
PF-06804103 | HER-2 | Advanced Solid Tumors | Valine-Citrulline | PF-06380101 (Aur 101) (Auristatin) | Ph I | AEs (44/93, 47.3%) and progressive disease (35/93, 37.6%) | 2021 |
Pfizer-CytomX ADC | EGFR | Cancer Indications | Undisclosed | Undisclosed | Preclinical | Received notification of Pfizer’s intent to terminate the companies’ research collaboration, option and license agreement | 2018 |
PYX-202 | DLK-1 | SCLC | β-glucuronidase (BG) linker | MMAE (Auristatin) | Preclinical | Undisclosed | 2022 |
RG6109 | CLL-1 | AML | Undisclosed | Pyrrolobenzodiazepine (PBD) | Ph I | Unfavourable benefit-risk profile | 2019 |
Rovalpituzumab tesirine | DLL3 | SCLC | Valine-Alanine | SG3199 (Pyrrolobenzodiazepine (PBD)) | Ph III | Lack of survival benefit | 2019 |
SAR428926 | LAMP-1 | Solid tumors | SPDB | DM4 (Maytansine) | Ph I | Undisclosed | 2018 |
SBT6290 | Nectin-4; TLR 8 (Payload target) | Breast Cancer | Undisclosed | TLR8 agonist (TLR agonists) | Ph I/ II | Similar clinical profile | 2022 |
SC-004 | CLDN6; CLDN9 | Endometrial Cancer | Valine-Alanine | SG3199 (Pyrrolobenzodiazepine (PBD)) | Ph I | Low tolerability | 2020 |
SGN-15 | Lewis Y antigen | Advanced Non-Small Cell Lung Cancer (NSCLC) | Hydrazone | Doxorubicin (Anthracycline) | Ph II | Focus on advancing its other pipeline programs | 2005 |
SGN-ALPV | Alkaline phosphatase, placental-like 2; ALPP | Advanced Endometrial Cancer | Undisclosed | MMAE (Auristatin) | Ph I | Prioritization assessment | 2023 |
SGN-CD123A | CD123 | AML | Valine-Alanine | SGD-1882 (Pyrrolobenzodiazepine (PBD)) | Ph I | Portfolio prioritization and restructuring initiatives | 2018 |
SGN-CD19B | CD19 | B-Cell Lymphoma | Valine-Alanine | SGD-1882 (Pyrrolobenzodiazepine (PBD)) | Ph I | Portfolio prioritization and restructuring initiatives | 2018 |
SGN-CD352A | CD352 | Myeloma | Valine-Alanine | SGD-1882 (Pyrrolobenzodiazepine (PBD)) | Ph I | Portfolio prioritization and restructuring initiatives | 2018 |
SGN-CD48A | CD48 | Myeloma | β-glucuronidase (BG) linker | MMAE (Auristatin) | Ph I | Portfolio prioritization and restructuring initiatives | 2019 |
SGN-CD70A | CD70 | B-Cell Lymphoma | Valine-Alanine | SGD-1882 (Pyrrolobenzodiazepine (PBD)) | Ph I | Portfolio prioritization and restructuring initiatives | 2016 |
SGN-STNV | STn | Advanced Solid Tumors | Valine-Citrulline | MMAE (Auristatin) | Ph I | Prioritization assessment | 2023 |
SYD1875 | 5T4 | Solid tumors | Valine-Citrulline | DUocarmycin-hydroxyBenzamide Azaindole (DUBA) (Duocarmycin ) | Ph I | Lack of significant benefit or progress, or potential patient safety concerns | 2022 |
TAA013 | HER-2 | Breast Cancer | SMCC | DM1 (Maytansine) | Ph III | Undisclosed | 2020 |
Trastuzumab imbotolimod | HER-2; TLR7/8 (Payload target) | Adenocarcinoma of the Breast | Undisclosed | Undisclosed | Ph II | Determination that program will not meet its pre-defined success criter | 2024 |
Tusamitamab ravtansine | CEACAM5 | Adenocarcinoma | SPDB | DM4 (Maytansine) | Ph III | Trial that did not meet the dual primary endpoint of improving progression-free survival | 2023 |
Vadastuximab talirine | CD33 | AML | Valine-Alanine | SGD-1882 (Pyrrolobenzodiazepine (PBD)) | Ph III | Portfolio prioritization and restructuring initiatives | 2018 |
Vorsetuzumab mafodotin | CD70 | Lymphoma | mc | MMAF (Auristatin) | Ph I | Undisclosed | 2013 |
XMT-1522 | HER-2 | Adenocarcinoma of the Breast | Fleximer Polymer | Auristatin F-HPA (Auristatin) | Ph I | Discontinued as per strategic evaluation | 2019 |
Aprutumab ixadotin | FGFR2 | Advanced Solid Tumors | Caproyl | Auristatin W analog (Auristatin) | Ph I | Dose-limiting toxicities | 2017 |
Ladiratuzumab vedotin | LIV-1 | Advanced Breast Cancer | Valine-Citrulline | MMAE (Auristatin) | Ph II | Undisclosed | 2024 |
MEDI7247 | ASCT2 | Acute Myelogenous/Myeloid Leukemia (AML) | Valine-Alanine | Pyrrolobenzodiazepine (PBD) | Ph I | Undisclosed | 2020 |
Pertuzumab zuvotolimod | HER-2; TLR 8 (Payload target) | Advanced HER2 Positive Solid Tumor | Undisclosed | Undisclosed | Ph I/II | Limited monotherapy anti-tumor activity and cytokine-related adverse events | 2022 |
Samatatug zovodotin | Tissue factor | Cervical Cancer | Valine-Citrulline | Auristatin | Ph I | Unlikely to improve upon existing TF-targeting ADCs | 2024 |
XMT-1592 | NaPi2b | Adenocarcinoma | Undisclosed | Auristatin F-HPA (XMT-1267) (Auristatin) | Ph I | Increasingly competitive nature of non-small cell lung cancer indication | 2022 |
INN = International Nonproprietary Name; RCC = Renal Cell Carcinoma; AML = Acute Myeloid Lymphoma; ALL = Acute Lymphocytic Leukemia; NSCLC = Non-small cell Lung Cancer |
Business Landscape of Antibody-Drug Conjugates
A flurry of deal-making activity is occurring in the ADC space, with these modalities re-emerging as a leading field of interest. With blockbuster deals from Abbvie’s $10.1 billion acquisition of ImmunoGen to Pfizer’s acquisition of Seagen for $43 billion in 2023, and multiple licensing agreements and strategic collaborations, ADC deals range from early to late-stage to marketed products and include a variety of oncology targets and indications. The integration of early pioneering ADC companies with large pharmaceutical firms highlights the increasing therapeutic potential ADC programs for various disease indications.
The tables below summarize recent partnership deals, venture capital funding events, and successful IPOs in the ADC space. Table 15 lists key licensing deals and mergers and acquisitions (M&As) in the ADC space from January 2020. Table 16 lists key venture capital funding events and IPOs in the ADC space since January 2020.
Figure 15: Total value of disclosed deals in the past 10 years3 (left) and approximate total value of upfront payments & potential deal values from disclosed transactions over the past 5 years3 (right)
Table 15: Antibody-Drug Conjugate Licensing and Merger and Acquisition (M&A) Deals
Partners | Asset(s) | Target | Deal Type | Date | Phase of Lead Asset at Time of Deal | Deal Value | References (Press Release) |
Day One & MabCare Therapeutics | DAY-301 (MTX-13) | PTK-7 | Exclusive Licensing Rights | Jun-2024 | Phase I | $55 million upfront; $1.15 billion in milestone payments & royalties | See Press Release |
ArriVent & Alphamab | Proprietary Linker-Payload Platform, Glycan Conjugation Technology | N/A | Collaboration Agreement | Jun-2024 | Discovery | $615.5 million | See Press Release |
Merck KGaA & Biolojic Design | Clinically Validated AI Platform | N/A | Multi-target drug discovery collaboration | Jun-2024 | Discovery | Upfront payment + up to €346 million in milestone payments | See Press Release |
Merck & Abceutics | Undisclosed | Undisclosed | Acquisition | Apr-2024 | N/A | $208 million | See Press Release |
Merck KGaA & Caris Life Sciences | Undisclosed | Undisclosed | Multi-year collaboration | Apr-2024 | Preclinical | $1.4 billion | See Press Release |
Genmab & ProfoundBio | Clinical & Preclinical ADC candidates including Rina-S; ADC technology platforms | Rina-S: FRα | Acquisition | Apr-2024 | Rina S: Phase I/II | $ 1.8 billion cash | See Press Release |
Ipsen & Sutro Biopharma | STRO-003 | ROR1 | Licensing Agreement | Apr-2024 | Preclinical | $900 million potential upfront and milestone payments; ~$90m in near-term payments; equity investment; tiered royalties | See Press Release |
Astrazeneca & Fusion Pharmaceuticals | FPI-2265 | mCRPC | Acquisition | Mar-2024 | Phase II | $2 billion upfront | See Press Release |
Immunome & Zentalis Pharmaceuticals | ZPC-21 | ROR1 | Exclusive License Agreement | Jan-2024 | Preclinical | $35 million upfront; $275 million in milestone payments; mid-to-high single-digit royalties | See Press Release |
Johnson & Johnson & Ambrx | ARX517, ARX788, ARX305 | PSMA, HER-2, CD-70 | Acquisition | Jan-2024 | Phase I/II, Phase III, Phase I | $ 1.9 billion | See Press Release |
Roche & MediLink | YL211 | c-Met | Licensing Agreement | Jan-2024 | Preclinical | ~ $ 1 billion + royalties | See Press Release |
Janssen & LegoChem | LCB84 | Trop2 | Licensing Agreement | Dec-2023 | Phase I/II | $ 100 million upfront; $ 200 M option exercise payment; milestone payment royalties | See Press Release |
GSK & Hansoh Pharma | HS-20089 | B7-H4 | Licensing Agreement | Dec-2023 | Phase I | $ 85 million upfront | See Press Release |
Pfizer & Nona Biosciences | HBM9033 | MSLN | Licensing Agreement | Dec-2023 | Preclinical | $53 million upfront & near term payments; up to $1.05 billion in milestone payments; royalties | See Press Release |
Merck & C4 Therapeutics | Undisclosed | Undisclosed | License and Collaboration Agreement | Dec-2023 | N/A | $10 million upfront; $600 million in milestone payments; tiered royalties | See Press Release |
BMS & SystImmune | BL-B01D1 | EGFR X HER3 | Strategic Collaboration agreement | Dec-2023 | Phase III | $800 million upfront; $500 million in contingent near term payments; $1.7 billion in milestone payments | See Press Release |
AbbVie & ImmunoGen | ELAHERE® | FRα | Acquisition | Nov-2023 | Marketed | $ 10.1 billion | See Press Release |
Merck & Jiangsu Hengrui Pharmaceuticals | SHR-A1904 | Claudin 18.2 | Strategic collaboration | Oct-2023 | Phase II | €160 million upfront; up to € 1.4 billion in potential payments | See Press Release |
GSK & Jiangsu Hansoh Pharmaceuticals | HS-20089 | B7-H4 | Exclusive license agreement | Oct-2023 | Phase I | $ 85 million upfront; up to $ 1.485 billion in milestone payments; royalties | See Press Release |
Merck & Daiichi Sankyo | Patritumab deruxtecan, ifinatamab deruxtecan, raludotatug deruxtecan | B7H3; HER3; CDH6 | Global development and commercial collaboration | Oct-2023 | Phase II | $ 4 billion upfront; $ 1.5 billion continuation payment; up to $16.5 billion in milestone payments | See Press Release |
Endeavour Biomedicines & Hummingbird Bioscience | Undisclosed | HER3 | Licensing Agreement | Oct-2023 | Preclinical | $ 430 million + royalties | See Press Release |
SOTIO & Synnafix | Technology Platforms: GlycoConnect, HydraSpace, toxSYN linker-payloads | Undisclosed | Licensing Agreement | Oct-2023 | Undisclosed | $ 740 million | See Press Release |
BioNTech & MediLink | Undisclosed | HER3 | Strategic collaboration & License Agreement | Oct-2023 | Undisclosed | $ 70 million upfront; over $ 1 billion in milestone payments | See Press Release |
Takeda & ImmunoGen | ELAHERE® | Folate R1 | Exclusive collaboration | Aug-2023 | Marketed | $ 34 million upfront + milestone payments and royalties | See Press Release |
Gilead Sciences & Everest Medicines | TRODELVY® | Trop 2 | Clinical development and commercialization agreement | Aug-2023 | Marketed | $280 million upfront; $175 million milestone payments | See Press Release |
GSK & Mersana | XMT-2056 | HER2 | Option Agreement | Aug-2023 | Preclinical | $100 million upfront; up to $1.36 billion in milestone payments | See Press Release |
BeiGene & DualityBio | Investigational, Preclinical ADCs for select solid tumors | N/A | License Agreement | Jul-2023 | Pre-clinical | $1.3 billion plus tiered royalties | See Press Release |
Eli Lilly & Emergence Therapeutics | N/A | N/A | Merger & Acquisition | Jun-2023 | N/A | $ 12 million | See Press Release |
AstraZeneca & La Nova Medicines | LM-305 | G protein-coupled receptor | License deal | May-2023 | Pre-clinical | $55 million upfront and near-payments; $545 million in milestone payments | See Press Release |
FibroGen & Fortis Therapeutics | FOR46 | Epitope on CD46 | Licensing Agreement | May-2023 | Phase I | Upto $80 million and total $200 million based on regulatory approvals | See Press Release |
Eisai Co., Ltd. & Bliss Biopharmaceuticals | BB-1701 | HER2 | Joint development Agreement | May-2023 | Phase I/II | $2 billion | See Press Release |
Bristol Myers Squibb & Tubulis | Tubutecan payloads in combination with proprietary P5 conjugation platform | Topoisomerase-1 | License agreement | Apr-2023 | N/A | $22.75 million upfront, $1 billion milestone payment | See Press Release |
Pfizer & Seagen | N/A | N/A | Acquisition | Apr-2023 | N/A | $43 billion | See Press Release |
Lonza & Synaffix | Proprietary Synaffix technology platform and R&D capabilities, including payload and site-specific linker technology | N/A | Acquisition | Apr-2023 | N/A | $107 million cash; up to $64 million in performance-based consideration | See Press Release |
Bristol Myers Squibb & Tubulis | P5 conjugation and Tubutecan platform | N/A | Licensing Agreement | Apr-2023 | N/A | $22.75 million upfront; over $1 billion in milestone payments plus royalty payments | See Press Release |
GeneQuantumm Healthcare & Pyramid Biosciences | GQ1010 | Trop 2 | Exclusive license agreement | Apr-2023 | Preclinical | $ 20 million upfront; up to $ 1 billion in milestone payments + royalties | See Press Release |
BioNTech & DualityBio | DB-1303; DB-1311 | HER2 | License Agreement | Apr-2023 | Phase II | $ 170 million upfront; $ 1.5 billion milestone payments; royalties | See Press Release |
Genmab & Synaffix | GlycoConnect, HydraSpace, toxSYN linker payloads | Undisclosed | License Agreement | Mar-2023 | Preclinical | $ 415 million + royalties | See Press Release |
MacroGenics & Synaffix | GlycoConnect, HydraSpace, toxSYN linker payloads | Undisclosed | Expansion of License Agreement | Mar-2023 | Clinical | $ 2.2 billion | See Press Release |
Takeda & Innate Pharma | R&D of ADCs focused on treating Celiac disease | Undisclosed | License Agreement | Mar-2023 | Discovery | $5 million upfront; $410 million in milestone payments; tiered royalties | See Press Release |
Vertex & ImmunoGen | Next generation ADCs | N/A | License and Option Agreement | Mar-2023 | N/A | $15 million Upfront Payment; up to $337 million in Option Fees & Milestone Payments; Tiered Royalties | See Press Release |
AstraZeneca & KYM Biosciences | CMG901 | Claudin 18.2 | Licensing Agreement | Feb-2023 | Phase I | $63 million upfront; up to $1.1 billion in milestone payments; royalties | See Press Release |
Corbus Pharmaceuticals & CSPC Megalith Biopharmaceutical | CRB-701 (SYS6002) | Nectin-4 | Licensing Agreement | Feb-2023 | Phase I | $7.5 million upfront; up to $130 million in development & regulatory milestone payments; $555 million in commercial milestone payments | See Press Release |
Hummingbird Bioscience & Synaffix | GlycoConnect™, HydraSpace™,select toxSYN™ linker-payloads | N/A | Licensing Agreement | Jan-2023 | N/A | $150 million | See Press Release |
Amgen & Synaffix | GlycoConnect™, HydraSpace™,select toxSYN™ linker-payloads | N/A | Licensing Agreement | Jan-2023 | N/A | $2 billion | See Press Release |
Merck & Mersana | Immunosynthen STING-agonist ADC platform | 2 undisclosed targets | License Agreement | Dec-2022 | N/A | $30 million upfront; $80 million in milestone payments | See Press Release |
Merck & Kelun-Biotech | 7 ADCs | N/A | Licensing Agreement | Dec-2022 | Discovery | $175 million upfront; Up to $9.3 billion in milestone payments; Tiered royalties | See Press Release |
Amgen & LegoChem Biosciences | ConjuAll ADC Technology | N/A | Licensing Agreement | Dec-2022 | Discovery | $1.25 billion upfront; Milestone payments & Royalties | See Press Release |
Exelixis & Iconic Therapeutics | XB002 | Tissue factor | Licensing Agreement | Dec-2022 | Phase I | $1.25 billion | See Press Release |
Exelixis & Catalent | Three target programs with Ab and/or ADC candidates | Undisclosed | License Agreement | Nov-2022 | Undisclosed | $ 30 million | See Press Release |
Celltrion & Pinot Bio | PINOT-ADC Technology | 15 separate cancer targets | Licensing Agreement | Oct-2022 | Discovery | $1 billion | See Press Release |
Zai Lab & Seagen | TIVDAK® | CD142 | Strategic collaboration and License Agreement | Sep-2022 | Marketed | $ 3o million upfront + milestone payments and royalties | See Press Release |
GSK & SpingWorks | BLENREP® | BCMA | Non-exclusive license and collaboration agreement | Sep-2022 | Marketed | $ 75 million equity investment;up to $ 550 millionin milestone payments | See Press Release |
Emergence Therapeutics & Synaffix | ADC platform (GlycoConnect, HydraSpace); SYNtecan E linker payload | Undisclosed | Licensing Agreement | Sep-2022 | Undisclosed | $ 360 million + royalties | See Press Release |
Elevation Oncology & CSPC Megalith Biopharmaceutical | EO-3021 | Claudin18.2 | Exclusive Agreement | Jul-2022 | Phase I | $ 27 million upfront; up to $ 148 million in development & regulatory milestone payments; up to $ 1.0 billion in commercial milestone payments and royalties | See Press Release |
Chiome Bioscience & Heidelberg Pharma | Amanitin toxin-linker platform technology | Undisclosed | Research and option agreement | Jul-2022 | Discovery | € 105 million | See Press Release |
Swedish Orphan Biovitrum AB (Sobi) & ADC Therapeutics | ZYNLONTA® | CD19 | Exclusive license agreement | Jul-2022 | Marketed | $ 55 million upfront; $ 50 million of first EC approval; up to $ 330 million in milestone payments | See Press Release |
Astellas & Sutro | Novel iADCs | N/A | Licensing Agreement | Jun-2022 | Discovery | $90 million upfront; Up to $422.5 million in milestone payments; royalties | See Press Release |
Turning Point Therapeutics & LaNova Medicines | LM-302 | Claudin18.2 | Exclusive license agreement | May-2022 | Phase I | $ 25 million upfront; $ 195 million in milestone payments; royalties | See Press Release |
Huadong Medicine & Heidelberg Pharma | HDP-101, HDP-103 | BCMA; PSMA | Strategic partnership agreement | Feb-2022 | pre-IND | $ 20 million upfront; up to $ 449 million in milestone payments; royalties | See Press Release |
MacroGenics & Synaffix | GlycoConnect, HydraSpace, toxSYN linker payloads | Undisclosed | License Agreement | Feb-2022 | Clinical | $ 586 million + royalties | See Press Release |
Eli Lilly & ImmunoGen | Camptothecin ADC platform | Type I Topoisomerase | Licensing Agreement | Feb-2022 | Discovery | $13 million upfront; $32.5 million additional targets; $1.7 billion milestone payments; Tiered royalties | See Press Release |
Janssen & Mersana | Dolasynthen platform | Multiple | Licensing Agreement | Feb-2022 | Discovery | $ 40 million upfront payment; up to $1 billion in potential milestone payments, percent royalties | See Press Release |
Odeon & OBI Pharma | OBI-999. OBI-833 | Globo H | Licensing Agreement | Feb-2022 | Phase I/II | Fully paid equity equivalent to $12 million; up to $188 million milestone payments; royalties on net sales | See Press Release |
Mitsubishi Tanabe & ADC Therapeutics | ZYNLONTA® | CD19 | Commercialization Agreement | Feb-2022 | Accelerated US approval (Apr 2022) | $30 million upfront payment; Up to $205 million in milestone payments | See Press Release |
Iksuda Therapeutics & LegoChem Biosciences | LCB14 | HER 2 | co-development and technology transfer agreement | Dec-2021 | N/A | $50 million up-front payment; up to $950 million in milestones | See Press Release |
SOTIO & LegoChem Biosciences | Conjugation technology ConjuAll™ and potent linker-payload platform | Undisclosed | Exclusive Collaboration & License Agreement | Nov-2021 | Discovery | Up to $ 1027.5 upfront and milestone payments + royalties | See Press Release |
Mersana & Synaffix | GlycoConnect™ | N/A | Licensing Agreement | Nov-2021 | N/A | $1 billion plus royalties | See Press Release |
Seagen and RemeGen | Disitamab Vedotin | HER2 | License and Co-Development Agreement | Sep-2021 | Marketed | Upfront $200 million ; $2.4 billion in potential developmental and regulatory milestones | See Press Release |
HealthCare Royalty & ADC Therapeutics | ZYNLONTA® and Cami | CD19 | Financing Agreement | Aug-2021 | ZYNLONTA™ : Marketed; Cami : Phase II | $325 million | See Press Release |
Bristol Myers Squibb & Eisai | MORAb-202 | FRα | Strategic collaboration | Jun-2021 | Phase 1/ 2 | $ 650 million upfront; up to $ 2.45 billion in milestone payments; royalties | See Press Release |
Boehringer Ingelheim & NBE-Therapeutics | NBE-002 + immune stimulatory iADCTM platform | ROR1 | Acquisition | Dec-2020 | Phase I | $1.5 billion (€1.2 billion). Includes contingent clinical and regulatory milestones | See Press Release |
Merck & VelosBio | VLS-101 | ROR1 | Acquisition | Nov-2020 | Phase II | $2.75 billion | See Press Release |
CStone Pharmaceuticals & LegoChem Biosciences | LCB71 | ROR1 | Licensing | Oct-2020 | Pre-clinical | $10 million upfront; up to $353.5 million in milestone payments, plus tiered royalties | See Press Release |
Gilead & Immunomedics | Trodelvy (Sacituzumab govitecan) | TROP2 | Acquisition | Sep-2020 | Accelerated US approval (Apr 2020) | ~$21 billion | See Press Release |
Merck & SeaGen | Ladiratuzumab vedotin | LIV-1 | Strategic collaboration | Sep-2020 | Phase II | $600 million upfront; $1 billion equity investment; up to $2.6 billion in milestone payments | See Press Release |
AstraZeneca & Daiichi Sankyo | DS-1062 | TROP2 | Strategic Collaboration | Jul-2020 | Phase I | $1 billion upfront (staged); up to $1 billion in regulatory milestones; up to $4 billion in sales milestones | See Press Release |
SeaGen & Five Prime | Multi-product | N/A | Licensing | Feb-2020 | N/A | $5 million upfront; up to $525 million in future milestone payments | See Press Release |
Shanghai Miracogen & Synaffix | GlycoConnect™ and HydraSpace™ | N/A | License Agreement | Apr-2019 | N/A | $125 million | See Press Release |
AstraZeneca & Daiichi Sankyo | Trastuzumab deruxtecan (DS-8201) | HER2 | Strategic Collaboration | Mar-2019 | Development | Upfront payment of $1.35 billion ; Contingent payments of up to $5.55 billion | See Press Release |
Table 16: List of Antibody-Drug Conjugate Venture Capital Funding Events and IPOs
Company | Asset (s) | Target | Funding Event | Date | Phase of Lead Asset at Time of Deal | Deal Value |
Endeavor BioMedicines | ENV-101; ENV-501 | Hedgehog(Hh); HER-3 | Series C | Apr-2024 | Phase II | $ 132.5 million |
TORL BioTherapeutics | TORL-1-23; TORL-2-307; TORL-3-600; TORL-4-500 | Claudin 6; Claudin 18.2; CDH17; DLK1 | Series B-2 | Apr-2024 | Phase I | $158 million |
ProfoundBio | Clinical and Preclinical ADC programs | N/A | Series B | Feb-2024 | N/A | $112 million |
Firefly Bio | Degrader Antibody Conjugate | N/A | Series A | Feb-2024 | Fast-track designatiion | $94 million |
OnCusp Therapeutics | CUSP06 | CDH6 | Series A | Jan-2024 | Phase I | $100 million |
Mbrace Therapeutics | ADCs for oncology targets | N/A | Series B | Nov-2023 | Preclinical | $85 million |
Tagworks Pharmaceuticals | Unique Click-to-Release platform | TAG72 | Series A | Jun-2023 | Preclinical | $65 million |
Adcentrx | ADRX-0706 | N/A | Series A+ | Apr-2023 | Preclinical | $38 million |
Adcendo | Lead candidate uPARAP-ADC | uPARAP | Series A | Apr-2023 | Preclinical | €31 million |
Solve Therapeutics | Novel mAbs, ADCs incorporating next-generation linker and payload constructs, and bispecific antibodies | N/A | Series A | Dec-2022 | N/A | $126 million |
Dantari | T-HDC (Targeted High-capacity Drug Conjugate) platform | N/A | Series A | Dec-2022 | N/A | $47 million |
Mablink | Patented hydrophilic drug-linker technology | N/A | Series A | Oct-2022 | Preclinical | €31 million |
Araris | Proprietary Linker Technology | N/A | Series A | Oct-2022 | N/A | $24 million |
Tubulis | Advance proprietary pipeline of ADCs towards clinical evaluation | N/A | Series B | May-2022 | N/A | $63 million |
Medlink Therapeutics | Proprietary technology platform | N/A | Series B | Mar-2022 |