Payloads and Linkers

ADC development can feel overwhelming, with a myriad of questions, technologies and possible routes to consider. Even before addressing the intricacies of an ADC molecule requiring complex chemistry and bioconjugation, developers often find their focus diverted by the challenges of navigating limitations and evaluating linker-payload options. At NJ Bio, we simplify this process by integrating bioconjugation, assay development, and linker-payload synthesis within a single lab space. Combined with the extensive experience of our team, we can answer your questions and deliver data quickly and efficiently. By addressing the chemistry challenges associated with both new and established technologies, we enable our clients to remain focused on biology and designing the best ADC possible. Our streamlined approach eliminates the need to coordinate multiple vendors, areas of expertise, or sites, providing seamless access to high-quality chemistry expertise in linker-payloads.

Customized, Advanced, and Comprehensive Solutions

At NJ Bio, Inc., we offer a full suite of services for payload and linker development, focusing on the unique chemistry of each component and the specific needs of your ADC project. Our advanced technical platform and expert team support seamless linker-payload synthesis, helping to accelerate ADC programs from early discovery to the clinic. We don’t just provide high-quality payload-linker components; we collaborate closely with you to select the optimal combination based on your target’s biology. Our comprehensive approach with strong chemistry and bioconjugation expertise helps maximize the therapeutic potential of your bioconjugates.

Integrated Payload-Linker Services

The synthesis of payloads for ADCs presents unique challenges compared to most small molecules. These payloads often require labor-intensive, multi-step processes due to their complex structures. While validated payloads can be obtained to expedite early-stage testing, developing customized or novel payloads tailored to specific clinical goals remains a significant challenge. This involves establishing a synthetic route for new chemical entities (NCEs), developing a reliable production process, and implementing robust analytical methods to detect and manage impurities throughout the development and manufacturing lifecycle.

With years of expertise in designing innovative payloads and novel chemical entities (NCEs) for ADC research, we provide seamless, end-to-end support across all stages of ADC development. Our comprehensive services span synthesis, process development, optimization, and GMP manufacturing. Supported by dedicated teams specializing in bioconjugation, antibody production, and analytical method development & validation, we ensure smooth transitions from early discovery to clinical-scale manufacturing.

Payload-Linker Design Process

We can help at different stages of the R&D process and select the fastest pathway to developing a bioconjugate clinical candidate. We supply validated as well as custom and novel linker payloads. Our team can support chemical scale-up and development of linker payloads. NJ Bio can create value when new, custom and challenging chemistry is required.

Validated Payload-Linkers

Our portfolio includes clinically validated combinations like MC-VCP-MMAE (vedotin), SMCC-DM1 (emtansine), SPDB-DM4, MC-MMAF (mafodotin), PBD dimers (tesirine and talirine), camptothecins (deruxtecan), CL2A-SN38 (govitecan), IGNs (DGN549C) and others, available for rapid conjugation and testing. We perform rapid conjugations and test the conjugates in vitro to help accelerate discovery through our integrated synthesis and bioconjugation services. This can accelerate early-stage screening by benchmarking against established standards.

Custom Payload-Linkers

Not all validated payload-linker combinations are ideal for every target. Our team customizes linkers and payloads to optimize solubility, release kinetics, and therapeutic efficacy, tailoring them to specific clinical and molecular needs. This step helps address any issues at an earlier stage thus avoiding the need for an expensive late-stage redesign.

Novel Payload-Linkers

For unique release mechanisms or novel payloads, we expedite the synthesis of new chemical entities (NCEs), allowing you to expand IP opportunities and reach clinical candidates faster. Our synthetic expertise enables the creation of advanced ADC payloads within a typical one-year timeline, ensuring minimal delays in development. If timed properly, this can result in minimal delays when performed in conjunction with other development activities.

Case Study: Process Optimization in the Synthesis of PBD (Pyrrolobenzodiazepine) and IGN (Indolinobenzodiazepine) Analogs for Enhanced Yield and Stability

Our process development team specializes in optimizing synthetic routes to improve yield, purity, and stability. We focus on solving challenges in the synthesis and development of custom payload linkers, ensuring our processes are scalable and efficient.

In this case study, we optimize reagents to enhance these factors in the synthesis of PBD and IGN analogs, effectively mitigating issues related to the molecules’ sensitivity to acids and bases.

Problem 1 and 2: During the synthesis of a PBD analog with an additional amino acid in the linker, oxidation of the PBD moiety to a pyrrole-containing compound and concomitant imine reduction in the 7-membered ring presented a significant challenge. Our team resolved this by optimizing protecting group strategies/ base labile protecting group and reaction conditions, including excess pyrrolidine and extended stirring, enabling efficient base-promoted Fmoc deprotection. Additionally, we identified ZnBr2 as an ideal deprotecting reagent for acid-labile groups and demonstrated the use of formic acid as a solvent modifier for purification. These innovations ensured the successful production of the desired compound in high quality and yield. Our focus on reaction mechanisms allows us to solve multiple challenges associated with linker-payload synthesis in a time-sensitive manner. This enables us to add value and accelerate our clients’ ADC programs.

Problems 3 and 4 were addressed by optimizing the reaction conditions. Adjusting the base and solvent minimized elimination issues during the substitution reaction, while exploring different coupling reagents enhanced the efficiency and yield of di/tripeptide spacer synthesis.

Problem 4: During the synthesis of a certain class of PBD analogs, the final product showed reduced activity and NMR revealed 11a racemization due to base-triggered instability of unprotected PBD monomers. After reviewing relevant literature, our team re-designed the synthetic strategy to retain stereochemistry and potency by employing N and O protected monomers as far as possible. Mild deprotection in later steps successfully mitigated racemization, ensuring the production of highly active and stereochemically pure compounds.

Scale-up and Development Support

Our scalable process development capabilities include both batch and flow chemistry. Flow chemistry, in particular, enhances the safety, scalability, and efficiency of high-potency compounds, making it ideal for challenging payload-linkers. Additionally, our experts in impurity profiling and reagent synthesis support end-to-end development, with all activities IND-compliant for clinical submissions.

GMP Manufacturing

NJ Bio offers GMP manufacturing for chemical payloads and linkers, supporting early-phase clinical trials (Phases 1 and 2). Our newly inaugurated Small Molecules Chemistry Suite is designed for the seamless transition from development to scale-up and manufacturing, making NJ Bio a trusted partner for your payload-linker needs. With the ability to handle OEB-5 materials (OEL <10 ng/m³) and production capacities ranging from milligrams to tens of kilograms, including tox batch manufacturing, we are equipped to meet diverse project requirements. Co-locating R&D and GMP manufacturing within the same facility streamlines workflows, accelerates timelines, and fosters close collaboration between teams for best output. Our advanced technologies and analytical processes are backed by quality systems that meet stringent GMP standards as outlined by regulatory authorities. With these capabilities, NJ Bio provides an efficient, single-site solution for all your payload-linker development, synthesis, and manufacturing needs.

NJ Bio, Inc., offers the following payload-linker services:

• Payload Synthesis and Optimization
• Synthesis of linkers with compatible conjugation chemistry and suitable release mechanisms
• Process Development and Optimization
• Ability to conduct sensitive reactions such as low-temperature and light-sensitive reactions
• GMP Manufacturing for Phases 1 and 2
• HPAPI lab setup
• Scale up and Unit Operation Development
• Route Design & DOE
• GMP Readiness
• Single-use technology
• Scalability/safety/economy for tox & engineering scales
• Critical process parameters (CPP) assessed by using DoE & QbD.
• Fully instrumented AR&D & quality team support – QC/QA