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Globalising ADC development in the US and beyond

Srivats Rajagopal explores the growth of the antibody-body conjugate (ADC) market, development trends and why innovators are turning towards India.

The ADC field has reached an inflection point. In 2022, Enhertu, Kadcyla, and Trodelvy together accounted for more than $4 billion of the $4.7 billion in global ADC revenues, and over 450 candidates were in development across tumour types including breast, lung, gastric, ovarian, and colorectal cancers (1). Analysts now project the market could surpass $140 billion within the decade, with several multi-billion dollar deals by giants like Merck and Roche in the last few years (2). Such growth reflects ADCs’ ability to couple monoclonal antibodies with highly potent payloads, improving survival in indications where traditional chemotherapies struggle (3).

But this progress has been hard won. ADCs are uniquely complex, demanding expertise across biologics, high-potency chemistry, and linker science. Second- and third-generation ADCs now advancing through clinical pipelines illustrate how much the field has evolved. Many of these programmes are led by small and mid-sized biotechs rather than big pharma, and this has elevated the role of CRDMOs. No longer simply contract manufacturers, CRDMOs now embed themselves upstream, offering antibody engineering, early analytical assays, and linker-payload optimisation that reduce risk before major clinical investment. Their capabilities —high-containment infrastructure, integrated process development, and advanced bioanalytical platforms —make them critical enablers of innovation (4).

A parallel geographic shift is also underway. Discovery remains concentrated in US and European biotech clusters, but HPAPI synthesis and, increasingly, bioconjugation are moving to India, where costs can be several-fold lower and state-of-the-art containment suites are expanding (5). Industry reports note that CRDMOs in India are adding high-potency API units and bioconjugation suites, with some facilities expected to come online in 2025, offering manufacturing at costs estimated to be up to 60% lower than in the West.

ADC Development Trends

The design of ADCs has advanced considerably since the first approvals. Early-generation products relied on stochastic conjugation at lysine or cysteine residues, resulting in heterogeneous drug-to-antibody ratios (DARs). While these molecules validated the modality, they also carried variability in efficacy and safety (6).

Today, site-specific conjugation methods are redefining the field. Engineered cysteines, glycan-directed chemistries, and enzymatic systems such as transglutaminase enable homogeneous DARs with improved pharmacokinetics and simpler regulatory comparability. Cysteine engineering offers scalability, while enzymatic approaches provide superior homogeneity but require robust enzyme supply chains and additional polishing steps (7).

Linker chemistry has also matured. Hydrophilic linkers, often PEGylated, improve solubility and reduce aggregation. Branched linkers offer flexibility in drug loading or dual payload attachment, enabling designs that combine cytotoxic payloads with immune stimulators. Cleavable linkers tuned to pH or protease-rich tumour environments allow controlled release, while non-cleavable linkers improve plasma stability (8). Companies have demonstrated how minor modifications, such as β-glucuronide-based cleavable linkers, can dramatically change stability profiles (9). Dual-payload strategies are particularly attractive in solid tumours, combining complementary mechanisms to overcome resistance.

Payload diversification is another defining trend. Auristatins and maytansinoids remain common, but topoisomerase I inhibitors have surged in prominence, with trastuzumab deruxtecan a case in point (1,3). Kinase inhibitors, radioconjugates, and novel payloads such as PROTACs or molecular glues are entering development, expanding the therapeutic potential. Immune-stimulating ADCs (iADCs), which deliver immune-modulatory molecules to tumour microenvironments, exemplify the shift toward more sophisticated biology (6,8). We have been working on some projects that involve conjugating antibodies to enzymes or tags for use in clinical diagnostic kits, applying the same chemistries and analytical approaches used in therapeutic ADCs.

Antibody scaffolds are evolving too. Nanobodies and affibodies improve tumour penetration, while bispecifics and biparatopics allow dual-epitope engagement, potentially enhancing efficacy (9). Single-chain variable fragments (scFvs) and enzyme-conjugate hybrids are in early exploration. Each format introduces conjugation and analytical challenges but also broadens the ADC playbook.

Beyond oncology, bioconjugates are expanding into new disease areas. Antibody–oligonucleotide conjugates (AOCs) are particularly promising. Avidity Biosciences, for example, is developing AOCs for Duchenne muscular dystrophy and myotonic dystrophy, where antibodies deliver siRNA directly to muscle tissue. Alnylam’s GalNAc-siRNA conjugates, though not antibodies, illustrate the potential of conjugation for targeted genetic medicines. Inflammation and autoimmune diseases are also being targeted, with ADC-like strategies designed to selectively deplete pathogenic immune cells. Early work even explores ADCs against infectious diseases, although this remains experimental (10).

At the discovery stage, innovators are prioritising internalisation efficiency and off-target risk reduction. Cell-based assays, antibody engineering, and in silico modelling are now standard (4). Linker-payload pairing and DAR tuning are increasingly tested upstream. Rather than deferring to later development, CRDMOs now help innovators test multiple conjugation strategies early—lysine, cysteine, site-specific—aligned with DAR targets, payload hydrophobicity, and clinical administration routes. Early DAR tuning, supported by LC-MS, HIC, and CE-SDS analytics, identifies optimal conjugates before costly toxicology studies (11). Even excipient and buffer optimisation, once a late-stage task, is now introduced early to reduce aggregation risks (11). Here, while PBS remains common, experienced development teams employ proprietary formulations or stabilisers to minimise aggregation during conjugation, especially with hydrophobic payloads. These “tricks” can determine manufacturability as much as conjugation chemistry itself.

Operational Shifts

Scientific innovation is only part of the story. Operational strategies are being reconfigured to manage ADC complexity. CRDMOs have evolved precisely because ADCs demand synchronisation of biology, chemistry, and analytics under stringent safety and regulatory frameworks.

Geography is an increasingly decisive factor. HPAPI manufacture in Western facilities is costly and constrained. In India, costs are significantly lower, and CRDMOs are investing in state-of-the-art OEB-6 containment suites, negative-pressure isolators, gloveboxes, and validated cleaning systems. These facilities not only handle cytotoxic payloads safely but also integrate linker synthesis, conjugation, and analytics, reducing handoffs and delays.

Discovery work, such as monoclonal antibody generation, can be carried out in US-based labs in close collaboration with innovators to select high-yielding clones. For example in our Morgan Hill facility in California, we work on high titre clone creations for mAbs and these can then be transferred to development facilities in India for scale-up, linker–payload assessment, and conjugation, ensuring continuity from discovery through development and GMP manufacturing. Such dual-site models allow smoother transitions and can help accelerate timelines.

Scale-up is a known bottleneck. Moving from milligram discovery batches to gram or kilogram scales often reveals aggregation, solubility, or reproducibility issues. CRDMOs are responding by embedding design-of-experiment (DoE) approaches to optimise parameters such as pH, temperature, mixing, and quenching. Critical process parameters—including antibody-to-payload ratios, reaction duration, solvent composition, and reductant levels—are monitored in real time with process analytical technologies (PAT) such as in-line pH probes, turbidity sensors, UV–Vis spectroscopy, and HPLC feeds. These data-rich approaches stabilise processes and support smoother tech transfer to GMP.

Pre-formulation excipient screening, once an afterthought, is now introduced early to mitigate aggregation risks. Sugars, amino acids, surfactants, and chelators are tested systematically using DoE designs. By anticipating stress-induced degradation pathways—methionine oxidation, deamidation, disulfide scrambling—developers can adjust conjugation and purification processes. Antioxidants, controlled reduction steps, and rapid purification protocols are deployed to minimise degradation.

Analytical sophistication has expanded to match complexity. Regulatory expectations now require detailed characterisation of DAR distributions, conjugation sites, unconjugated antibodies, free drug, and degradation products. LC-MS (intact and reduced), peptide mapping, CE-SDS, and size-exclusion chromatography are standard. Multi-attribute monitoring (MAM) adds efficiency by tracking multiple quality attributes simultaneously. Native mass spectrometry resolves intact species and low-abundance DAR forms, while dynamic light scattering (DLS) offers real-time aggregation insight. Ion mobility mass spectrometry, though less common, is being explored to deepen understanding of ADC microheterogeneity.

Containment remains paramount. ADC payloads exhibit nanomolar cytotoxicity, demanding robust occupational safety protocols. CRDMOs are increasingly equipped with closed-system transfers, negative-pressure isolators, smart air showers, and validated cleaning to prevent cross-contamination. Facilities are becoming modular, designed to handle multiple hazard classifications and solvent systems. This flexibility is vital as payloads diversify beyond classic cytotoxics.

CRDMOs are also rethinking their role as portfolio partners. With more biotechs developing entire ADC pipelines, demand is growing for platform-based development: modular linker-payload libraries, scaffolded workflows, and standardised analytics that reduce variability across programmes. Larger organisations have established integrated platforms; mid-sized and emerging CRDMOs are rapidly building comparable offerings. AI and digital tools are being adopted to model linker stability, predict payload solubility, and automate process monitoring, further accelerating development.

Co-location is perhaps the most transformative shift. By embedding discovery, conjugation, analytics, and GMP manufacturing within integrated facilities, CRDMOs eliminate tech transfer delays and enable parallel development streams. Programmes that once took 30 months from lead selection to IND can now be compressed to 12–18 months. For small and mid-sized biotechs—often resource-constrained—this acceleration is decisive.

These operational shifts underscore why CRDMOs are increasingly seen not only as capacity providers but as innovation engines. They are enabling continuity from concept to clinic, reducing attrition, and helping shape strategic choices about design, manufacturability, and regulatory readiness.

Conclusion

ADCs have firmly established themselves in oncology and are expanding into inflammation, genetic disorders, and other therapeutic areas. Their trajectory reflects a dual dynamic: advances in antibody engineering, linker chemistry, and payload diversification on one hand, and operational innovation in supply chains, analytics, and manufacturing on the other.

CRDMOs are at the centre of this evolution. By embedding earlier in the pipeline, they are helping innovators navigate antigen selection, internalisation assays, conjugation strategy, and early analytics. Their high-containment facilities, modular workflows, and platform toolkits are enabling continuity from discovery to GMP. Crucially, they are not just executing development but shaping it—bringing expertise that influences design decisions upstream and ensuring reproducibility downstream.

Geographic rebalancing is reinforcing this trend. Discovery remains anchored in Western biotech clusters, but India is rapidly emerging as a centre for HPAPI synthesis and, increasingly, for bioconjugation. With advanced containment, analytical platforms, and GMP readiness, Indian CRDMOs are offering cost efficiency alongside quality that meets global standards. Having already established a reputation as a reliable alternative to China for rapid and affordable monoclonal antibody generation, many are now extending into bioconjugation by adding HPAPI suites and dedicated facilities. This expansion positions them to provide more integrated, end-to-end ADC development. Dual-site models that combine US-based discovery with Indian manufacturing are becoming increasingly common, and over time, may evolve into fully integrated supply chains spanning continents.

The outlook is promising. ADC pipelines will diversify, timelines will shorten, and CRDMOs that combine upstream scientific insight with downstream execution will shape the next generation of targeted therapeutics. Platformisation, AI-enabled design, and digital process monitoring will further accelerate development. As more modalities emerge—immune-stimulating ADCs, dual payload constructs, antibody–oligonucleotide conjugates—the ability of CRDMOs to integrate biology, chemistry, and analytics under one roof will define success.

ADCs are no longer just a therapeutic class; they are a proving ground for new models of biopharma collaboration. The winners will be those who pair innovation in chemistry with innovation in operating models, delivering precision therapies to patients faster, safer, and at greater scale.

References:

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4. Manufacturing Chemist. How CRDMOs are shaping the next generation of ADCs. Manufact Chem. 2024;48(3):22–29.
5. Mint Bureau. Aragen Life Sciences eyes IPO as it expands global footprint with biologics, ADCs. Mint. 29 Aug 2025.
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7. Pillow TH, Sadowsky JD, Zhang D, et al. Site-specific ADCs. Bioconjug Chem. 2017;28(4):1169–79.
8. Lyon RP, Setter JR, Bovee TD, et al. Self-hydrolysing maleimides improve ADC stability. Nat Biotechnol. 2014;32(10):1059–62.
9. Shadid M, Hobeika A, Alami J, et al. Nanobodies and bispecific antibodies in ADCs. Front Immunol. 2023;14:1145786.
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About the author

Srivats Rajagopal is Senior Director and Head of Cell and Protein Sciences in Discovery Biology for Aragen Life Sciences in Hyderabad. He previously led Protein Sciences at Syngene for over a decade and later headed Program Management at biotech start-up Perfect Day before taking on his current leadership role at Aragen.