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NJ Bio, Inc._Recent Advances in ADCs

Recent Advances in ADCs

World ADC_Best Contract Research Provider 2022

​By: Julien Dugal-Tessier, Reva Raghupathi, and Ralf Mueller
NJ Bio, 350 Carter Rd, Princeton, NJ 08540, U.S.A.

Last updated on 10th May 2023

Mechanism of action of Antibody-Drug Conjugates

An antibody-drug conjugate (ADC) is a molecule that combines the specificity of a monoclonal antibody and the cell killing ability of cytotoxic agents. This combination allows the delivery of tailor-made chemotherapeutics preferentially to cancer cells while largely sparing normal cells. A well-designed ADC increases the therapeutic index by lowering the toxicity through limiting the systemic circulation of cytotoxic agents without compromising their activity on the tumor tissue. Together, this ultimately allows to treat patients that would not tolerate systemic chemotherapies because of their large side effects. An ADC is composed of three elements (Figure 1): the antibody, the linker and the cytotoxin (payload), which are all very important to obtain the best therapy.1 This discussion will go over the vital aspects of ADC design and their elements.

Structure of Antibody-Drug Conjugate with linker and drug toxin payload, and conjugation shown with the antibody IgG1

Figure 1: Anatomy of an ADC2

One could ask, how does one even start developing an ADC? The starting point is the antigen that will be recognized by the antibody for delivering the cytotoxin. How much of the antigen is expressed on cancer versus normal cells? How many copies are found on these cancer cells? How quickly does the ADC internalize? Is the indication a liquid or a solid tumor? Is the antigen expressed on 100% of the cancer cells or only on 50% of the cancer cells? All these questions help guide the selection of the ADC’s individual elements. 3

Figure 2 below describes the basic steps that lead to ADC activity. First, the ADC must have a high enough plasma concentration to get into the tumor tissue. Second, the ADC must have enough binding, internalization, and processing events to release enough active catabolite to cause apoptosis. This sounds simple enough but is much more complicated to practically develop. Keeping this mechanism in mind, different elements can be optimized to find the right balance of activity versus toxicity.3

Internalization and mechanism of action of Antibody Drug Conjugates:  Internalization of the ADC, lysosome formation, and lysosomal degradation of the ADC to free toxins or drugs are shown in this art

Figure 2: Mechanism of action of an ADC. 2

The following discussion will focus on the conjugation and linker-payload portion of ADCs rather than on the design of the antibody itself. The antibody used in ADCs can have a variety of different modifications to modulate ADC activity such as extending half-life, binding two different epitopes, and having engineered conjugation sites. We will start our discussion with conjugation, followed by linkers and cytotoxins, and finish with the entire ADC construct.4

Bioconjugation: Attaching Cytotoxins to Antibodies

Attaching a linker-payload to an antibody might seem simple, but there are many different considerations and methods that need to be carefully balanced. The first concept is a measurement of how many conjugations occurred on the antibody. Any ADC that is prepared will have a drug-to-antibody ratio (DAR), which is the average number of cytotoxins found per antibody (Figure 3). This ratio is measured by a variety of analytical techniques, which generally all give similar results but almost never the same number.5 That is why NJ Bio recommends using two different methods to determine the DAR. As the field evolves, finding orthogonal methods for DAR determination is becoming more routine.6 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).3

DAR distribution between heterogeneous (Stochastic) and homogeneous conjugations.

Figure 3: DAR Distribution between Heterogeneous (Stochastic) and Homogeneous Conjugations.2

The most common methods to attach linkers to antibodies utilize the natural nucleophilic amino acids found on the antibody, with lysine and cysteine being by far the two residues of choice. Lysine conjugations are typically accomplished by mixing the antibody with an activated ester. Lysine conjugation has the advantages of being operationally simple and forming a stable amide bond between the antibody and the linker-payload. However, linker attachment to lysine can change the overall charge of the antibody. Lysine-based conjugations result in a DAR distribution between 0 and 9 when an average DAR of 3.5 is targeted.

The other nucleophilic amino acids used for conjugation are the interchain cysteines which requires initial manipulation of the antibody. The reactive thiols are masked as interchain disulfides between the heavy-light and heavy-heavy chains and must be released with a reducing agent (e.g., TCEP, DTT). Once the antibody is reduced, the thiols are available to react with an electrophile, such as a maleimide or haloacetamide. The DAR is 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. Cysteine conjugation is fast, reliable and does not alter the charge of the antibody but can with certain motifs undergo a reverse reaction that releases the linker-payload into circulation.7 Currently, most ADCs employ cysteine conjugation for the attachment of the linker-payloads.3

Over the years many new technologies and protocols have been developed to give ADCs with a homogeneous DAR. Examples of these technologies include engineered cysteines, non-natural amino acids, bridging linker groups and use of enzymes to control the distribution of the linker-payload.3 These technologies improve the pre-clinical therapeutic index but are beyond the scope of this discussion.3

Types of Linkers

Cytotoxins generally do not have a conjugatable group and thus a spacer or linker must be added to allow the cytotoxin to be attached to the antibody. This spacer is called the linker and comes generally in two flavors: cleavable (releasable) and non-cleavable (non-releasable).8

A non-cleavable linker is a linker that does not contain any biologically or chemically labile bond and an active catabolite is released by 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.9

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 kill neighboring cells through passive diffusion.
The most popular linker is the protease cleavable linker that contains a valine-citrulline-para-aminobenzyl-carbamate moiety (vc-PABC).10 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.11 The advantages of cleavable linkers are that they have good plasma stability and robust activity in a variety of cell lines and preclinical models.12

Another means of releasing a 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 do shed cytotoxins in circulation but are nonetheless still powerful linker motifs.8

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.13

Selection of Cytotoxin for Antibody-Drug Conjugates

A variety of different cytotoxins can be combined and matched with different linkers. ADC cytotoxins commonly have activity in the sub-nanomolar range by disrupting tubulin, damaging DNA, inhibiting topoisomerases, and preventing other essential cell processes. These cytotoxins will have different potencies, permeabilities, and hydrophobicities. The selection of the exact cytotoxin will be dependent on the linker type and how sensitive the tumor is to the active catabolite. The major classes of cytotoxins are the following: auristatins,14 maytansinoids,15 calicheamicins,16 pyrrolidinobenzodiazepines (PBDs),17 indolinobenzodiazepines (IGNs),18 duocarmycins,18 camptothecins,19 alpha-amanitins,20 and protein degraders.21 The validated cytotoxins in approved ADCs consist of calicheamicins, maytansinoids, auristatins and camptothecins. All these cytotoxins can be further derivatized to have the best possible properties.

Key components of ADC development from proof of concept to successful clinical trial

Figure 4: Aspects of ADC design.

Selection of the Linker-Payloads for ADCs

Now comes the important question of how to select the linker, the cytotoxin, the conjugation method, and the DAR. This usually involves several rounds of optimization but understanding the biology can help decide the best starting point. If, for example, the tumor has consistent expression throughout the tissue then one could consider non-cleavable linkers to lower toxicity. If there is heterogenous expression, then a cleavable linker generating a membrane permeable catabolite (have bystander activity) would be advantageous. Knowing the internalization rate and the number of antigens per cell can help determine how potent the cytotoxin will need to be. If the tumor cells have high expression of the antigen, then a less potent cytotoxin could be used. 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. Another widely used method for the selection of a linker-payload is to start with a representative model and screen all advanced linker-payloads. The standard linker-payloads are MC-MMAF, MC-VCPAB-MMAE, SMCC-DM1, SPDB-DM4, Dxd(1), CL2A-SN38, Tesirine, and DGN549. These cytotoxins are available from commercial sources and their clinical doses are already established.3

When it comes to the selection of the entire construct – which involves optimizing DAR, hydrophobicity, and pharmacokinetics – it will depend on what the expected clinical dose will be.22 To overcome the tumor antigen barrier, maximize tumor penetration and increase uptake in the tumor versus normal tissue, dosing in the linear PK range should be the objective.22 This information can be extrapolated from pre-clinical studies in non-human primates. Toxicity is driven by the linker-payload and not the target, thus selecting the right linker-payload platform is of great importance.23 Having a proper linker-payload for an indication is key for clinical success.

To conclude, there are many parameters that need to be optimized for ADCs and there are no hard and fast rules to follow. This synopsis highlights considerations that can help guide linker-payload selection. A well-designed ADC can have a tremendous clinical benefit but, in the end, it is not a one-size-fits-all approach.

Antibody-Drug Conjugates that are approved or undergoing clinical trials24

Several ADCs are currently approved or undergoing clinical trials and summarized in Table 1.  The first ADC to receive market approval, gemtuzumab ozagamicin, was first 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 and Millenium Pharmaceuticals/Takeda, achieved $658 million in sales in 2020. Trastuzumab emtansine, launched by Roche, continues to enjoy blockbuster status with $1.76 billion in sales in 2020. Three entrants introduced in 2019, trastuzumab deruxtecan, launched by Daiichi Sankyo, enfortumab vedotin, launched by SeaGen and Astellas, and polatuzumab vedotin, launched by Roche, are also poised for success, with trastuzumab deruxtecan projected to achieve a multi-billion dollar forecast by 2024.  Sacituzumab govitecan, from Immunomedics Inc., and belantamab mafodotin, from GlaxoSmithKline, recently launched in 2020. The importance of ADCs as a key therapeutic modality is demonstrated by their clinical and market success, as well as the size and number of ADC business deals, described in a later section.

Table 1: Antibody-Drug Conjugates that are approved or undergoing clinical trials (Source: Beacon Intelligence Database)

INN (Isotype) Drug Linker Target Indication Stage Approval Year
Brevituximab vedotin (IgG1) MMAE Cleavable CD30 HL Approved 2011
Trastuzumab emtansine (IgG1) DM1 Non-cleavable Her2 Breast Cancer Approved 2013
Gemtuzumab ozagamicin (IgG4) Calicheamicin pH Sensitive CD33 AML Approved 2017
Inotuzumab ozagamicin (IgG4) Calicheamicin pH Sensitive CD22 NHL Approved 2017
Polatuzumab vedotin (IgG1) MMAE Cleavable CD79b B-Cell lymphoma Approved 2019
Enfortumab vedotin (IgG1) MMAE Cleavable Nectin 4 Bladder Cancer Approved 2019
Trastuzumab deruxtecan (IgG1) DXd Cleavable Her2 Breast Cancer Approved 2019
Sacituzumab govitecan (IgG1) SN-38 pH Sensitive Trop 2 Breast Cancer Approved 2020
Belantamab mafodotin MMAF Non-Cleavable BCMA Multiple Myeloma Approved 2020
Loncastuximab tesirine (IgG1) PBD Cleavable CD19 B-Cell Lymphoma Approved 2021
Disitamab vedotin (IgG1) MMAE Cleavable Her2 Breast Cancer Approved 2021
Tisotumab vedotin (IgG1) MMAE Cleavable CD142 Cervical Cancer Approved 2021
Ujvira (IgG1) DM1 Non-cleavable HER-2 Breast Cancer Approved 2021
Mirvetuximab soravtansine (IgG1) DM4 Cleavable Folate R1 Ovarian Cancer Approved 2022
Trastuzumab vedotin (IgG1) MMAE Cleavable HER-2 Breast Cancer PhIII NA
Tusamitamab ravtansine (IgG1) DM4 Cleavable CEACAM5 Non-small cell lung cancer PhIII NA
Telisotuzumab vedotin (IgG1) MMAE Cleavable c-MET Non-small cell lung cancer PhIII NA
SKB264 (IgG1) KL610023 Cleavable TROP-2 Breast Cancer PhIII NA
Datopotamab deruxtecan (IgG1) DXd/DX8951 Cleavable TROP-2 Breast Cancer PhIII NA
Patritumab Deruxtecan (IgG1) DXd/DX8951 Cleavable HER-3 Breast Cancer PhIII NA
Trastuzumab rezetecan (IgG1) Camptothecin Non-cleavable HER-2 Breast Cancer PhIII NA
TAA013 (IgG1) DM1 Cleavable HER-2 Breast Cancer PhIII NA
Upifitamab Rilsodotin (IgG1) Auristatin F-HPA Cleavable NaPi2b Ovarian Cancer PhIII NA
FS-1502 (IgG1) MMAE Cleavable HER-2 Breast Cancer PhIII NA
MRG003 (IgG1) MMAE Cleavable EGFR Biliary Tract Cancer PhIII NA

INN = International Nonproprietary Name; HL = Hodgkin Lymphoma; NHL = non-Hodgkin Lymphoma; AML = Acute Myeloid Lymphoma; PhII = Phase 2 clinical trial; PhIII = Phase 3 clinical trial.

Discontinued Antibody-Drug Conjugates

Although the field of ADCs has had many successes and new approvals in the last few years, there are many discontinued programs that provide important information. Most of these ADCs have been discontinued due to the lack of a favorable therapeutic index, or in other words, a lack of efficacy at a tolerable dose. Some ADCs have also been discontinued due to pipeline reprioritization or due to the competitive landscape. Most ADCs have used auristatin- and maytansinoid-based ADCs, 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 fam-trastuzumab deruxtecan-nxki, a very promising new ADC. Table 2 displays targets and ADCs that have entered the clinic and have not proceeded, and a new generation of ADCs can be developed with this knowledge.

Table 2: List of Discontinued Antibody-Drug Conjugates.

Name​ Target​ Indication​ Drug-Linker​ Last Phase​ Reasons for Discontinuation Discontinuation Year
BAT8001 HER2 Breast cancer Maytansinoid Phase III Not in pipeline 2021
Depatuximab mafodotin (ABT-414) EGFRvIII Brain cancer MC-MMAF​ Phase III No survival benefit 2019
Rova-T DLL-3 Small-cell lung cancer​ Tesirine Phase III No survival benefit 2018
SGN-CD33A CD33 AML Talirine Phase III Toxicity; led to a halt of all talirine conjugates 2021
CDX-011 gpNMB Breast cancer MC-Val-Cit-Paba-MMAE​ Phase IIb Failed primary endpoint of progression free survival (PFS) 2018
AGS16C3F​ ENPP3 Metastatic renal cell carcinoma​ MC-MMAF​ Phase II​ Did not meet primary endpoint 2019
Lorvotuzumab mertansine (IMGN901)​ CD56​ Small-cell lung cancer​ SPP-DM1​ Phase II​ Lack of superiority to etoposide​ 2013/14
Bavituzumab mertansine ​CD44v6 Solid tumors SPP-DM1 Phase II Toxicity 2005
BR96-Doxorubicin Lewis Y Breast cancer Doxorubicin Phase II No efficacy 2002
Indusatumab vedotin GCC Pancreatic Valine-Citrulline Phase II Lack of efficacy 2018
Lifastuzumab vedotin (DNIB0600A) NaPi2B Ovarian cancer​ MC-Val-Cit-Paba-MMAE​ Phase II Did not meet primary endpoint 2016
MLN-2704 PSMA Prostate cancer SPP-DM1 Phase II Due to peripheral neuropathy 2006
PCA062 P-Cadherin Breast cancer SMCC Phase II Limited anti-tumor activity 2022
Pinatuzumab vedotin (DCDT2980S) CD22 B-Cell MC-Val-Cit-Paba-MMAE​ Phase II Unknown 2015
PSMA ADC PSMA Prostate cancer MMAE Phase II Unknown 2018
SAR3419 CD19 DLBCL / ALL / NHL SPDB-DM4 Phase II Rights returned 2018
SAR-566658 Mucin 1 Ovarian SPDB-DM4 Phase II Unknown 2018
SGN-15 Lewis Y antigen Breast/ Colorectal/ Lung Cancer Hydrazone Phase II To focus on advancing its other pipeline programs 2005
TAK-264 (MLN-0264) GCC AML MC-Val-Cit-Paba-MMAE​ Phase II Lack of efficacy 2018
SBT6050 HER-2; TLR 8 (Payload target) Breast cancer Undisclosed Phase I/II Limited monotherapy anti-tumor activity and cytokine-related adverse events 2022
SBT6290 Nectin-4; TLR 8 (Payload target) Breast cancer Undisclosed Phase I/ II Similar clinical profile 2022
AMG 172​ CD70 (TNF family)​ Renal cell carcinoma​ SMCC-DM1​ Phase I​ Not mentioned 2016
AMG 224​ BCMA r/r multiple myeloma​ SMCC-DM1​ Phase I​ BiTE technology​ 2019
AMG 595​ EGFR VIII​ EGFR positive cancers​ SMCC-DM1​ Phase I​ Lack of efficacy ​ 2018
Laprituximab emtansine​ (IMG289) EGFR​ Head and neck, non-small cell lung cancer​ SMCC-DM1​ Phase I​ Not mentioned​ 2015
Sofituzumab vedotin​ MUC16​ Ovarian, Pancreatic cancer​ MC-Val-Cit-Paba-MMAE​ Phase I​ Not mentioned 2015
Cantuzumab mertansine​ MUC1 (CanAg)​ Colorectal cancer​ SPP-DM1/SPDB-DM4​ Phase I ​ Licensed to GSK in 1999​ 2014
ABBV-176 PRLR Solid tumors Tesirine Phase I ​ Safety 2018
ADCT-502 Her2 Breast cancer Tesirine Phase I Lack of efficacy at tolerated dose 2018
ADCT-601 ​AXL Solid tumors Tesirine Phase I Terminated (change in clinical plan and drug supply) 2020
AGS15ME SLTRK6 Urothielial MC-Val-Cit-Paba-MMAE​ Phase I Unknown 2020
AGS67E CD37 B/T cell malignancy MC-Val-Cit-Paba-MMAE​ Phase I Unknown 2018
ASG5ME SLC44A4 Prostate cancer MC-Val-Cit-Paba-MMAE​ Phase I Narrow therapeutic index 2013
AVE9633 CD33 AML SPDB-DM4 Phase I Unknown 2009
BAT8003 TROP-2 Breast cancer 3AA Phase I Subsequent development risks of the drug 2021
BAY 79-4620 CA9 Solid tumors MC-Val-Cit-Paba-MMAE​ Phase I Adverse Events 2011
BAY1187982 FGFR2 Solid tumors Caproyl Phase I Dose-limiting toxicities 2017
BIIB015 Cripto Solid tumors SPDB-DM4 Phase I Unknown 2011
Bivatuzumab Mertansine CD44v6 Breast cancer SPP Phase I Occurrence of skin toxicity 2005
BMS-936561 CD70 Renal / NHL Duocarmycin Phase I Toxicity Profile 2018
CDX-014 TIM1 Ovarian / renal MMAE Phase I Unknown 2018
CMB-401 Muc 1 Ovarian cancer​ Calicheamicin Phase I Did not meet efficacy endpoint 2016
CMD-193 Lewis Y antigen Epithelial cancer AcBut acyl hydrazone-disulfide Phase I Unknown 2014
DCLL9718S CLL1 AML PBD Phase I Limited tolerability and anti-tumor acitivty 2019
DEDN6526A Endothelin B Melanoma vC-MMAE Phase I Unknown 2014
DEDN-6526A EDNRB Melanoma MC-Val-Cit-Paba-MMAE​ Phase I Unknown 2014
Denintuzumab mafodotin (SGN-CD19A) CD19 ALL and NHL MC-MMAF​ Phase I Unknown 2018
DFRF4539A IRTA2 Multiple myeloma VC-MMAE Phase I Limited activity observed 2014
DHES0815 Her2 Breast cancer PBD Phase I Unknown / stopped recruiting 2019
DMOT4039A / RG7600 mesothelin Pancreatic MC-Val-Cit-Paba-MMAE​ Phase I Low efficacy 2014
DS-6157 GPR20 Gastrointestinal stromal cancer GGFG Phase I No clear responses in GIST patients at any dose level 2021
Enapotamab vedotin AXL Solid tumors VC-MMAE Phase I Insufficient activity 2020
Glembatumumab vedotin gpNMB Squamous Cell Carcinoma of the Lung Valine-Citrulline Phase I Did not meet primary end point 2018
HKT288 CDH6 Ovarian cancer​ sulfo-SPDB-DM4 Phase I Unknown 2018
IMGN242 CanAg Gastric cancer SPDB Phase I Slow pace of progress 2009
IMGN388 Integrin Solid tumors SPDB-DM4 Phase I Unknown 2011
IMGN779 CD33 AML DGN462 Phase I Portfolio prioritization 2019
LOP628 c-KIT AML SMCC-DM1​ Phase I Unknown / Hypersensitivity observed 2016
LY3076226 FGFR3 Solid tumors SPDB-DM4 Phase I Unknown 2019
MEDI2228 BCMA MM PBD Phase I Efficacy / Toxicity / Competitive Landscape 2021
MEDI3726 / ADCT-401 PSMA Prostate cancer Tesirine Phase I Toxicity 2019
MEDI-4276 Her2 Breast cancer Tubulysin Phase I Toxicity 2018
MEDI-547 EphA2 Ovarian MC-MMAF​ Phase I mAb toxicity 2012
MM-310 EphA2 Solid tumors Undisclosed Phase I Cumulative peripheral neuropathy 2019
PF-06263507 5T4 Solid tumors MC-MMAF​ Phase I No objective responses 2015
PF-06647263 EFNA4 Solid tumors Calicheamicin Phase I Re-prioritization 2019
PF-06650808 NOTCH-3 solid tumors Auristatin AUR-101 Phase I Re-prioritization 2016
PF-06664178 Trop-2 Breast cancer, Non-small cell lung cancer, Ovarian cancer Ac-Lys-VC-Aur0101 Phase I Toxicity 2016
PF-06688992 GD3 Breast cancer Undisclosed Phase I Unknown 2019
RG6109 CLL-1 AML Undisclosed Phase I Unfavorable benefit-risk profile. 2019
RG7841 LY6E Solid tumors VC-MMAE Phase I Unknown 2017
RG7882 MUC16​ Ovarian MC-Val-Cit-Paba-MMAE​ Phase I Unknown 2018
SAR428926 LAMP1 MM SPDB-DM4 Phase I Unknown 2018
SC-003 DPEP Ovarian cancer​ Tesirine Phase I Lacked safety profile and tumor activity to continue 2019
SC-004 CLDN6/9 Ovarian cancer​ Tesirine Phase I Low tolerability and lack of activity 2020
SC-006 RNF43 Colorectal cancer​ Tesirine Phase I Thombocytopenia below expected efficacious dose 2019
SC-007 TNFSF9 Colorectal cancer​ Tesirine Phase I Dose limiting toxicity; did not meet endpoint 2018
SGN-CD123A CD123 AML Talirine Phase I Toxicity 2018
SGN-CD19B CD19 NHL Talirine Phase I Stopped due to other talirine toxicity 2018
SGN-CD352 CD352 Multiple myeloma Talirine Phase I Stopped due to other talirine toxicity 2018
SGN-CD48A CD48 Multiple myeloma Auristtain-PEG Phase I Insufficient risk/benefit 2019
SGN-CD70A CD70 Renal cell carcinoma​ Valine-Alanine Phase I Portfolio review and evaluation of clinical data 2016
Vadastuximab talirine CD70 NHL / Renal Talirine Phase I Stopped due to talirine toxicity 2018
Vorsetumab mafodotin (SGN-75) CD70 NHL MC-MMAF​ Phase I Unknown 2013
XMT-1522 Her2 Breast cancer Dolaflexin-AF-HPA Phase I Prioritization of XMT-1536 2019

Business Deals in the Antibody-Drug Conjugate space

A flurry of deal-making activity is occurring in the ADC space, with ADCs once again emerging as a leading field of interest. These deals show the value that ADCs can offer, and the ADC platform is becoming an important therapeutic modality. With blockbuster deals from Gilead’s acquisition of Immunomedics for $21 billion in September 2020 and Merck’s acquisition of VelosBio for $2.75 billion in November 2020, to co-development deals such as Merck with SeaGen and AstraZeneca with Daiichi-Sankyo, ADC deals range from early to late-stage to marketed products and include a variety of oncology targets and indications.

The tables below summarize recent partnership deals, venture capital funding events, and successful IPOs in the ADC space. Table 3 lists key licensing deals and mergers and acquisitions (M&As) in the ADC space since January 2020. Table 4 lists key venture capital funding events and IPOs in the ADC space since January 2020.

Table 3: 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
AstraZeneca and Daiichi Sankyo Trastuzumab deruxtecan (DS-8201) HER2 Strategic Collaboration Mar 2019 Development Upfront payment of $1.35bn ; Contingent payments of up to $5.55bn
Shanghai Miracogen & Synaffix GlycoConnectTM and HydraSpaceTM N/A License Agreement Apr 2019 N/A $125 million
Five Prime and SeaGen Multi-product N/A Licensing Feb 2020 N/A $5 million upfront; up to $525 million in future milestone payments
Daiichi Sankyo and AstraZeneca DS-1062 TROP2 Strategic Collaboration July 2020 Phase I $1 billion upfront (staged); up to $1 billion in regulatory milestones; up to $4 billion in sales milestones
Immunomedics and Gilead Trodelvy (Sacituzumab govitecan) TROP2 Acquisition Sep 2020 Accelerated US approval (Apr 2020) ~$21 billion
SeaGen and Merck 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
Lego Chem and CStone Pharmaceuticals LCB71 ROR1 Licensing Oct 2020 Pre-clinical $10 million upfront; up to $353.5 million in milestone payments, plus tiered royalties
VelosBio and Merck VLS-101 ROR1 Acquisition Nov 2020 Phase II $2.75 billion
NBE-Therapeutics and Boehringer Ingelheim NBE-002 + immune stimulatory iADCTM platform ROR1 Acquisition Dec 2020 Phase I $1.5 billion (€1.2 billion). Includes contingent clinical and regulatory milestones
ADC Therapeutics & HealthCare Royalty ZYNLONTATM and Cami CD19 Financing Agreement Aug 2021 ZYNLONTATM : Approved; Cami : Phase II $325 million
Seagen and RemeGen Disitamab Vedotin HER2 License and Co-Development Agreement Sep 2021 Approved Upfront $200 million ; $2.4 billion in potential developmental and regulatory milestones
Synaffix & Mersana GlycoConnectTM N/A Licensing Agreement Nov 2021 N/A $1 bn plus royalties
Legochem Biosciences & Iksuda Therapeutics LCB14 HER 2 co-development and technology transfer agreement Dec 2021 N/A $50 million up-front payment; up to $950 million in milestones
ImmunoGen & Eli Lily Camptothecin ADC platform Type I Topoisomerase Licensing Agreement Feb 2022 Discovery $13M upfront;
$32.5M additional targets;
$1.7 bn milestone payments;
Tiered royalties
Janssen & Mersana Dolasynthen platform Multiple Licensing Agreement Feb 2022 Discovery $ 40M upfront payment; upp to $1B in potential milestone payments, percent royalties
OBI Pharma & Odeon OBI-999. OBI-833 Globo H Licensing Agreement Feb 2022 Phase I/II Fully paid equity equivalent to $12M; up to $188M milestone payments; royalties on net sales
Mitsubishi Tanabe & ADC Therapeutics ZYNLONTATM CD19 Commercialization Agreement Feb 2022 Accelerated US approval (Apr 2022) $30M upfront payment; Up to $205M in milestone payments
Sutro & Astellas Novel iADCs N/A Licensing Agreement Jun 2022 Discovery $90M upfront; Up to $422.5M in milestone payments; royalties
Pinot Bio & Celltrion PINOT-ADC Technology 15 separate cancer targets Licensing Agreement Oct 2022 Discovery $1 bn
Merck & Kelun-Biotech 7 ADCs N/A Licensing Agreement Dec 2022 Discovery $175M upfront;
Up to $9.3 bn in milestone payments;
Tiered royalties
LegoChem Biosciences & Amgen ConjuAll ADC Technology N/A Licensing Agreement Dec 2022 Discovery $1.25 bn upfront;
Milestone payments & Royalties
Iconic Therapeutics & Exelixis XB002 Tissue factor Licensing Agreement Dec 2022 Phase I $1.25 bn
Hummingbird Bioscience & Synaffix GlycoConnectTM, HydraSpaceTM,select toxSYNTM linker-payloads N/A Licensing Agreement Jan 2023 N/A $150M
Synaffix & Amgen GlycoConnectTM, HydraSpaceTM,select toxSYNTM linker-payloads N/A Licensing Agreement Jan 2023 N/A $2 bn
Keymed and Lepu Biopharma & AstraZeneca CMG901 Claudin 18.2 Licensing Agreement Feb 2023 Phase I $63 M upfront; up to $1.1 bn in milestone payments; royalties
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
ImmunoGen & Vertex Next generation ADCs N/A License and Option Agreement Mar 2023 N/A $15 M Upfront Payment; up to $337 Million in Option Fees & Milestone Payments; Tiered Royalties​
Pfizer & Seagen Transformative cancer medicine N/A Acquisition Mar 2023 N/A $43 billion
Bristol Myer Squibb & Tubulis Tubutecan payloads and P5 conjugation platform N/A Licensing Agrement Apr 2023 N/A $22.75 million upfront, more than $1 billion milestone payments plus tiered royalties

Table 4: 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
NBE Therapeutics NBE-002 ROR1 Series C Jan 2020 Preclinical $22 million
Silverback Therapeutics SBT6050 (anti-HER2 antibody conjugated to a potent TLR8 agonist), pipeline of ImmunoTACTM programs HER2 Series B Mar 2020 Preclinical $78.5 million
ADC Therapeutics Loncastuximab tesirine, Camidanlumab tesirine and others CD19, CD25 IPO May 2020 Phase II $268 million
Avidity Antibody Oligonucleotide ConjugatesTM, including AOC 1001 TfR1 IPO June 2020 Preclinical $298 million
Bolt Therapeutics Immune Stimulating Antibody Conjugate (ISAC) platform, BDC-1001 HER2 Series C July 2020 Phase I/II $93.5 million
VelosBio VLS-101 and other ROR1-directed ADCs ROR1 Series B July 2020 Phase II $137 million
Tubulis Tub-tagTMplatform, TUB-010, TUB-020 N/A Series A July 2020 Preclinical €10.7 million
Silverback Therapeutics SBT6050 (anti-HER2 antibody conjugated to a potent TLR8 agonist), pipeline of ImmunoTACTM programs HER2 Series C Sep 2020 Phase I $85 million
Silverback Therapeutics ImmunoTACTMtechnology platform HER2 IPO Dec 2020 Phase I $278 million
Suzhou Medilink Therapeutics Next generation ADCs N/A Series A Mar 2021 N/A $50 million
ProfoundBio Novel technology platforms for ADCs and IO therapeutics N/A Series A July 2021 N/A $55+ million
Pheon Therapeutics Next generation ADCs N/A Series A Mar 2022 N/A $68 million
Tubulis Advance proprietary pipeline of ADCs towards clinical evaluation N/A Series B May 2022 N/A $63 million

In summary, ADCs have emerged as an important therapeutic class of agents that can lead to new opportunities in the treatment of various cancers. Recent significant scientific and clinical advances in the field of ADCs have highlighted it as an important space for continued research and investment.


Review Articles for Antibody-Drug Conjugates

(1)        Pysz, I.; Jackson, P. J. M.; Thurston, D. E. CHAPTER 1. Introduction to Antibody–Drug Conjugates (ADCs). In Cytotoxic Payloads for Antibody–Drug Conjugates; 2019; pp 1–30. https://doi.org/10.1039/9781788012898-00001.

(2)        Jain, N.; Smith, S. W.; Ghone, S.; Tomczuk, B. Current ADC Linker Chemistry. Pharmaceutical Research 2015, 32, 3526–3540. https://doi.org/10.1007/s11095-015-1657-7.

(3)        Beck, A.; Goetsch, L.; Dumontet, C.; Corvaïa, N. Strategies and Challenges for the next Generation of Antibody-Drug Conjugates. Nature Reviews Drug Discovery 2017, 16 (5), 315–337. https://doi.org/10.1038/nrd.2016.268

(4)        Chari, R. V. J.; Miller, M. L.; Widdison, W. C. Antibody-Drug Conjugates: An Emerging Concept in Cancer Therapy. Angewandte Chemie International Edition 2014, 53 (15), 3796–3827. https://doi.org/10.1002/anie.201307628

(5)        Matsuda, Y.; Robles, V.; Malinao, M. C.; Song, J.; Mendelsohn, B. A. Comparison of Analytical Methods for Antibody-Drug Conjugates Produced by Chemical Site-Specific Conjugation: First-Generation AJICAP. Analytical Chemistry 2019, 91 (20), 12724–12732. https://doi.org/10.1021/acs.analchem.9b02192

(6)        Sarrut, M.; Fekete, S.; Janin-Bussat, M.-C.; Colas, O.; Guillarme, D.; Beck, A.; Heinisch, S. Analysis of Antibody-Drug Conjugates by Comprehensive on-Line Two-Dimensional Hydrophobic Interaction Chromatography x Reversed Phase Liquid Chromatography Hyphenated to High Resolution Mass Spectrometry. II- Identification of Sub-Units for the Characterization of even and odd load drug species. Journal of chromatography. B, Analytical technologies in the biomedical and life  sciences 2016, 1032, 91–102. https://doi.org/10.1016/j.jchromb.2016.06.049

(7)        Tumey, L. N.; Charati, M.; He, T.; Sousa, E.; Ma, D.; Han, X.; Clark, T.; Casavant, J.; Loganzo, F.; Barletta, F.; Lucas, J.; Graziani, E. I. Mild Method for Succinimide Hydrolysis on ADCs: Impact on ADC Potency, Stability, Exposure, and Efficacy. Bioconjugate chemistry 2014, 25 (10), 1871–1880. https://doi.org/10.1021/bc500357n

(8)        Sievers, E. L.; Senter, P. D. Antibody-Drug Conjugates in Cancer Therapy. Annual Review of Medicine 2013, 64 (1), 15–29. https://doi.org/10.1146/annurev-med-050311-201823

(9)        Alley, S. C.; Okeley, N. M.; Senter, P. D. Antibody–Drug Conjugates: Targeted Drug Delivery for Cancer. Current Opinion in Chemical Biology 2010, 14 (4), 529–537. https://doi.org/10.1016/j.cbpa.2010.06.170

(10)       Doronina, S. O.; Toki, B. E.; Torgov, M. Y.; Mendelsohn, B. A.; Cerveny, C. G.; Chace, D. F.; Deblanc, R. L.; Gearing, R. P.; Bovee, T. D.; Siegall, C. B.; Francisco, J. A.; Wahl, A. F.; Meyer, D. L.; Senter, P. D.; Zhang, L.; Miles, M. F.; Aldape, K. D. Development of Potent Monoclonal Antibody Auristatin Conjugates for Cancer Therapy Corrigendum : A Model of Molecular Interactions on Short Oligonucleotide Microarrays. Nat. Biotech. 2003, 21 (8), 2003.

(11)       Jeffrey, S. C.; de Brabander, J.; Miyamoto, J.; Senter, P. D. Expanded Utility of the β-Glucuronide Linker: ADCs That Deliver Phenolic Cytotoxic Agents. ACS Medicinal Chemistry Letters 2010, 1 (6), 277–280. https://doi.org/10.1021/ml100039h

(12)       Lyon, R. P.; Bovee, T. D.; Doronina, S. O.; Burke, P. J.; Hunter, J. H.; Neff-Laford, H. D.; Jonas, M.; Anderson, M. E.; Setter, J. R.; Senter, P. D. Reducing Hydrophobicity of Homogeneous Antibody-Drug Conjugates Improves Pharmacokinetics and Therapeutic Index. Nature Biotechnology 2015, 33 (7), 733–735. https://doi.org/10.1038/nbt.3212

(13)       Lewis Phillips, G. D.; Li, G.; Dugger, D. L.; Crocker, L. M.; Parsons, K. L.; Mai, E.; Blättler, W. A.; Lambert, J. M.; Chari, R. V. J.; Lutz, R. J.; Wong, W. L. T.; Jacobson, F. S.; Koeppen, H.; Schwall, R. H.; Kenkare-Mitra, S. R.; Spencer, S. D.; Sliwkowski, M. X. Targeting HER2-Positive Breast Cancer with Trastuzumab-DM1, an Antibody-Cytotoxic Drug Conjugate. Cancer Research 2008, 68 (22), 9280–9290. https://doi.org/10.1158/0008-5472.CAN-08-1776

(14)       Akaiwa, M.; Dugal-Tessier, J.; Mendelsohn, B. A. Antibody–Drug Conjugate Payloads; Study of Auristatin Derivatives. Chemical and Pharmaceutical Bulletin 2020, 68 (3), 201–211. https://doi.org/10.1248/cpb.c19-00853

(15)       Costoplus, J. A.; Veale, K. H.; Qiu, Q.; Ponte, J. F.; Lanieri, L.; Setiady, Y.; Dong, L.; Skaletskaya, A.; Bartle, L. M.; Salomon, P.; Wu, R.; Maloney, E. K.; Kovtun, Y. v.; Ab, O.; Lai, K.; Chari, R. V. J.; Widdison, W. C. Peptide-Cleavable Self-Immolative Maytansinoid Antibody-Drug Conjugates Designed to Provide Improved Bystander Killing. ACS Medicinal Chemistry Letters 2019, 10 (10), 1393–1399. https://doi.org/10.1021/acsmedchemlett.9b00310

(16)       Shor, B.; Gerber, H.-P.; Sapra, P. Preclinical and Clinical Development of Inotuzumab-Ozogamicin in Hematological Malignancies. Molecular immunology 2015, 67 (2 Pt A), 107–116. https://doi.org/10.1016/j.molimm.2014.09.014

(17)       Mantaj, J.; Jackson, P. J. M.; Rahman, K. M.; Thurston, D. E. From Anthramycin to Pyrrolobenzodiazepine (PBD)-Containing Antibody-Drug Conjugates (ADCs). Angewandte Chemie International Edition 2017, 56 (2), 462–488. https://doi.org/10.1002/anie.201510610

(18)       Elgersma, R. C.; Coumans, R. G. E. E.; Huijbregts, T.; Menge, W. M. P. B. P. B.; Joosten, J. A. F. F.; Spijker, H. J.; de Groot, F. M. H. H.; van der Lee, M. M. C. C.; Ubink, R.; van den Dobbelsteen, D. J.; Egging, D. F.; Dokter, W. H. A. A.; Verheijden, G. F. M. M.; Lemmens, J. M.; Timmers, C. M.; Beusker, P. H. Design, Synthesis, and Evaluation of Linker-Duocarmycin Payloads: Toward Selection of HER2-Targeting Antibody-Drug Conjugate SYD985. Molecular Pharmaceutics 2015, 12 (6), 1813–1835. https://doi.org/10.1021/mp500781a

(19)       Li, W.; Veale, K. H.; Qiu, Q.; Sinkevicius, K. W.; Maloney, E. K.; Costoplus, J. A.; Lau, J.; Evans, H. L.; Setiady, Y.; Ab, O.; Abbott, S. M.; Lee, J.; Wisitpitthaya, S.; Skaletskaya, A.; Wang, L.; Keating, T. A.; Chari, R. V. J.; Widdison, W. C. Synthesis and Evaluation of Camptothecin Antibody-Drug Conjugates. ACS Medicinal Chemistry Letters 2019, 10 (10), 1386–1392. https://doi.org/10.1021/acsmedchemlett.9b00301

(20)       Pahl, A.; Lutz, C.; Hechler, T. Amanitins and Their Development as a Payload for Antibody-Drug Conjugates. Drug Discovery Today: Technologies 2018, 30, 85–89. https://doi.org/10.1016/j.ddtec.2018.08.005

(21)       Pillow, T. H.; Adhikari, P.; Blake, R. A.; Chen, J.; del Rosario, G.; Deshmukh, G.; Figueroa, I.; Gascoigne, K. E.; Kamath, A. v.; Kaufman, S.; Kleinheinz, T.; Kozak, K. R.; Latifi, B.; Leipold, D. D.; Sing Li, C.; Li, R.; Mulvihill, M. M.; O’Donohue, A.; Rowntree, R. K.; Sadowsky, J. D.; Wai, J.; Wang, X.; Wu, C.; Xu, Z.; Yao, H.; Yu, S. F.; Zhang, D.; Zang, R.; Zhang, H.; Zhou, H.; Zhu, X.; Dragovich, P. S. Antibody Conjugation of a Chimeric BET Degrader Enables in Vivo Activity. ChemMedChem 2020, 15 (1), 17–25. https://doi.org/10.1002/cmdc.201900497

(22)       Cilliers, C.; Menezes, B.; Nessler, I.; Linderman, J.; Thurber, G. M. Improved Tumor Penetration and Single-Cell Targeting of Antibody–Drug Conjugates Increases Anticancer Efficacy and Host Survival. Cancer Research 2018, 78 (3), 758–768. https://doi.org/10.1158/0008-5472.CAN-17-1638

(23)       Mahalingaiah, P. K.; Ciurlionis, R.; Durbin, K. R.; Yeager, R. L.; Philip, B. K.; Bawa, B.; Mantena, S. R.; Enright, B. P.; Liguori, M. J.; van Vleet, T. R. Potential Mechanisms of Target-Independent Uptake and Toxicity of Antibody-Drug Conjugates. Pharmacology & Therapeutics 2019, 200, 110–125. https://doi.org/10.1016/j.pharmthera.2019.04.008

(24)       Khongorzul, P.; Ling, C. J.; Khan, F. U.; Ihsan, A. U.; Zhang, J. Antibody-Drug Conjugates: A Comprehensive Review; 2020; Vol. 18. https://doi.org/10.1158/1541-7786.MCR-19-0582