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Cancer remains one of the leading causes of death globally, placing immense economic and social strain on healthcare systems. According to World Health Organisation 2024 report, approximately 20 million new cancer cases and 9.7 million cancer-related deaths were recorded in 2022, and American Cancer Society 2026 report estimates roughly 2,114,850 new cancer cases in the United States. These figures underscore the urgent need for more effective and targeted therapeutic approaches, along with early interventions in improving the survival rate.

Chemotherapy, based on cytotoxic agents, continues to be a cornerstone of cancer treatment due to its strong anti-tumour efficacy. The idea of delivering cytotoxic drugs directly to targeted cells—minimizing systemic toxicity while enhancing therapeutic effectiveness—was first proposed by Paul Ehrlich in 1913 as a ‘magic bullet’ theory. However, its clinical utility is often limited by poor target specificity, a narrow therapeutic window, and the development of drug resistance. Achieving precise tumour targeting and expanding the therapeutic window of cytotoxic agents remains a critical challenge in oncology.

In response, extensive research has focused on developing therapies with enhanced selectivity and reduced toxicity. Monoclonal antibodies (mAbs) have emerged as powerful tools in cancer treatment, offering high specificity and targeted mechanisms of action. Since the approval of the first mAb, Muromonab, in 1986, over 160 mAbs have been approved by 2025, with around 42% directed toward oncology indications. Despite their specificity, mAbs often lack the intrinsic cytotoxicity of traditional chemotherapeutics and may still face resistance issues. To overcome these limitations, antibody–drug conjugates (ADCs) have emerged as a transformative class of therapeutics. ADCs combine the targeting precision of mAbs with the potent cell-killing ability of cytotoxic drugs, offering a promising strategy to improve efficacy while minimizing systemic toxicity. They consist of a monoclonal antibody (mAb) linked to a potent cytotoxic payload via a chemical linker. ADCs are designed to selectively bind to specific antigens present on the surface of target cells, while sparing cells that lack the antigen. Upon binding, the ADC is internalized into the cell and transported to catabolic vesicles, where it is degraded to release active metabolites that exert their cytotoxic effects.

The development and manufacturing of antibody–drug conjugates (ADCs) are highly complex process. They require the integration of a monoclonal antibody (mAb), linker and a cytotoxic payload, which must be chemically conjugated and then formulated into the final drug product. Due to the potent toxicity of the payloads, many steps must be conducted in high-containment facilities, adding further logistical and safety challenges.

Despite these complexities, ADC projects offer a unique opportunity for collaboration between scientists specializing in biologics (mAbs) and those focused on synthetic chemistry (payloads and linkers). The development and scale-up of the mAbs, payloads and linkers present significant, yet exciting, challenges for protein science and process scientists.

Most payloads used in approved ADCs are derived from natural products and possess high molecular complexity, resulting in lengthy and intricate synthetic pathways. The payloads of currently FDA-approved antibody-drug conjugates (ADCs) primarily fall into three categories: anti-mitotic agents such as auristatins (e.g., MMAE, MMAF, maytansinoid derivatives such as DM1, DM4), DNA-damaging agents including calicheamicins and pyrrolobenzodiazepine (PBD) dimers, and topoisomerase inhibitors such as DXd and SN-38.

The linker is a vital component of antibody-drug conjugates (ADCs), responsible for precisely attaching cytotoxic payloads to monoclonal antibodies (mAbs). Its design plays a critical role in ensuring targeted drug delivery and optimizing therapeutic efficacy. An ideal linker design must exhibit high stability in systemic circulation, maintaining a secure bond between the antibody and the payload. This stability minimizes premature drug release and reduces off-target toxicity, thereby enhancing the safety and effectiveness of the ADC. Linkers have been categorised into two types – cleavable and non-cleavable.

Diverse types of antibodies are being explored, however, humanised and fully human IgGs are commonly utilised as ADC backbone. Monoclonal antibodies with high specificity for tumour-associated antigens (TAAs) expressed on the surface of malignant cells serve as optimal target moieties for the development of antibody-drug conjugates (ADCs), facilitating selective intracellular delivery of cytotoxic payloads to neoplastic tissues while minimizing off-target effect.

1. The Bottleneck in Payload-Linker Chemistry

The therapeutic efficacy of Antibody–Drug Conjugates (ADCs) depends on precise control of chemical purity, stability, and drug-to-antibody ratio (DAR), placing significant emphasis on payload design and manufacturability. However, widely used natural product–derived payloads, such as Camptothecin (CPT) and Auristatin analogues, present substantial synthetic challenges.

These molecules exhibit high structural complexity, with multiple stereocenters and functionalized frameworks, leading to long multi-step syntheses (>15–20 steps) and low overall yields. A robust control strategy is required to maintain stereochemical integrity and reduce process variability. Functional group instability further complicates synthesis and handling. For instance, CPT lactone rings are prone to hydrolysis, while Auristatins contain peptide-like linkages susceptible to degradation and epimerization. These sensitivities restrict reaction conditions and reduce process robustness.

In addition, unstable intermediates, poor solubility, and reliance on chromatographic purification hinder scalability and batch reproducibility. Manufacturing challenges are compounded during scale-up, where reaction control, safety, and availability of specialized reagents affect cost of goods and supply reliability.

Payload design must also accommodate linker conjugation without compromising potency, often requiring additional synthetic modifications. Furthermore, susceptibility to efflux-mediated multidrug resistance (MDR) drives further structural optimization, adding complexity to already demanding synthetic routes.

Cohance, provides a fully backward-integrated platform designed to solve these upstream scaling and conjugation bottlenecks from gram to multi-ton scale.

2. Platform Core Competencies & Chemical Engineering

2.1 The Camptothecin (CPT) Platform & S-Trione Technology

Topoisomerase I inhibitors (such as SN-38 and Exatecan) selectively induce cancer cell death by stabilizing Topoisomerase I–DNA complexes, blocking DNA repair, disrupting replication, and ultimately triggering apoptosis.

The structural modification of core scaffold is often constrained by process feasibility and the need to maintain stereochemical integrity.

[S-Trione Intermediate] ──(Proprietary Synthetic Route)──> [Diverse CPT Derivatives / Exatecan / SN-38]

• Proprietary S-Trione Scaffold :  Cohance utilizes our proprietary (s)-Trione intermediate (US DMF 039042) as a versatile core scaffold. This technology enables efficient, scalable modification of the camptothecin core without sacrificing stereocenters.
• Library and Scale :  Access to over 2,000 custom CPT derivatives tailored to specific linker compatibilities and target cytotoxicity profiles.
• Active DMF Support : Fully audited manufacturing with active US DMFs for S-Trione, Camptothecin, Irinotecan, SN-38 andExatecan with upcoming filings for Topotecan, Belotecan??.

2.2 Technology Driven Process Development

Can we talk about our process development strategy in details – expand how we use AI like mentioned below? Any innocation or process we follow to ensure robust development of payload – as a takeaway for technical readers

Cohance has built a strong platform around payloads targeting topoisomerase (camptothecin derivatives) and tubulin inhibitors (MMAE and its derivatives). The team leverages AI-enabled tools for efficient route scouting, predictive reaction optimization, and impurity profiling, complemented by a Quality by Design (QbD) framework to ensure robust and scalable process development. Additionally, advanced Design of Experiments (DoE) methodologies are systematically applied to map process parameters, define design spaces, and enhance process robustness. Integration of data-driven modeling and machine learning further supports kinetic understanding, yield improvement, and control strategy development, enabling efficient scale-up while maintaining consistency, quality, and cost-effectiveness.

A systematic control strategy is implemented to effectively manage impurities, supported by highly sensitive and advanced analytical methods for comprehensive characterization and cleaning validation. These capabilities are further strengthened by a well-established quality management system, ensuring consistency, reliability, and uninterrupted supply of high-quality materials.

Camptothecin Platform

MMAE derivatives

Comprehensive safety and quality frameworks have been established to support the handling of high-potency compounds, with emphasis on rigorous containment and risk mitigation. The infrastructure is designed to enable reliable scale-up from laboratory development to commercial manufacturing for OEB-4 to OEB-6 molecules. These systems are underpinned by advanced engineering controls, including closed processing, dedicated containment equipment, and facility design aligned with global regulatory expectations.

I also found this table when I added a list of our payload and payload intermediates = does the key technical value read right?

Commercial Specifications & Supply Chain Risk Mitigation

Please consider below table