Precision Cancer Therapy Driving Investment and Innovation

Antibody-drug conjugates (ADCs) are rapidly emerging as a transformative force in precision medicine, revolutionizing cancer treatment by combining the targeting precision of monoclonal antibodies with the potent cytotoxic effects of small-molecule drugs. With the ability to precisely target and eliminate cancer cells while sparing healthy tissue, ADCs are driving unprecedented innovation in oncology and beyond. The global ADC market, valued at $9.7 billion in 2023, is projected to reach $19.8 billion by 2028, fueled by advancements in linker technologies, payload design, and combination therapies. However, challenges such as resistance mechanisms and manufacturing complexities remain critical areas of focus. This article delves into the historical evolution, emerging technologies, and future opportunities shaping the ADC landscape, highlighting their potential to deliver safer, more effective, and increasingly personalized treatments across a wide range of diseases.

In recent years, ADCs have emerged as a beacon of hope in the fight against cancer, offering a new paradigm for targeted therapy. By leveraging the specificity of monoclonal antibodies and the potency of cytotoxic agents, ADCs deliver “precision chemotherapy” directly to cancer cells, minimizing collateral damage to healthy tissues. This innovative approach is not only transforming the oncology landscape but is also being explored in autoimmune diseases and infectious conditions. With more than 150 ADCs in clinical trials and over a dozen approved for clinical use, the field is witnessing exponential growth, marked by groundbreaking scientific advancements and significant industry investment. This article explores the evolution of ADCs, their current state, and the transformative potential of next-generation technologies such as degrader-antibody conjugates (DACs) and advanced combination therapies.

What Are Antibody-Drug Conjugates? – ADCs are biopharmaceutical drugs that consist of three components:

Antibody: Targets specific antigens on cancer cells for precision delivery.

Linker: Ensures stability during circulation and releases the drug upon reaching the tumor.

Payload: A potent cytotoxic agent that destroys cancer cells while sparing healthy tissues.
This approach enhances the effectiveness of cancer therapies and is now expanding into broader applications beyond oncology.

Historical Context and Development – ADCs have evolved over decades through significant milestones:

• Early Attempts: Initial designs in the 1950s and 60s faced challenges with stability and specificity.
• First Approval: Mylotarg (gemtuzumab ozogamicin), approved in 2000 for acute myeloid leukemia, highlighted early challenges with toxicity.
• Next Generation: The approvals of Adcetris (brentuximab vedotin) in 2011 and Kadcyla (adotrastuzumab emtansine) in 2013 marked breakthroughs in linker and payload technologies.
• Enhertu Era: Enhertu (trastuzumab deruxtecan), approved in 2019, introduced an innovative payload-linker combination, setting new standards for ADC efficacy and safety.

Today, over 150 next-generation ADCs are in clinical trials. Notable examples include Teliso-V for non- small cell lung cancer and Orum’s GSPT1-targeting ADC for acute myeloid leukemia, showcasing ADCs’ ability to address novel diseases and expand their therapeutic scope.

Additional promising candidates include:

• Patritumab deruxtecan (HER3 target) in Phase 3 for metastatic non-small cell lung cancer.
• Ifinatamab deruxtecan (B7-H3 target) in Phase 2 for small cell lung cancer.
• Raludotatug deruxtecan (cadherin 6 target) in Phase 1 for advanced ovarian cancer.
  

These developments reflect the versatility and expanding applications of ADC technology.

Expanding Applications and Technologies – While ADCs are predominantly used in oncology, their applications are broadening:

• Autoimmune Diseases: ADCs are being explored for targeted delivery of immunosuppressive agents to specific immune cells.
• Infectious Diseases: ADC-like constructs may target infected cells to deliver antimicrobial or immune-stimulating payloads.
  

Emerging technologies are further enhancing ADC capabilities:

• Novel Payloads: ADCs now incorporate protein degraders, immunostimulants, and radionuclides, expanding their therapeutic potential. Protein degraders, in particular, offer a unique advantage by actively degrading rather than inhibiting target proteins, addressing issues of drug resistance and broadening the scope of ADC applications (Dragovich, Chem. Soc. Rev., 2022; doi: 10.1039/d2cs00141a).
• Degrader-Antibody Conjugates (DACs): DACs represent a cutting-edge innovation at the intersection of ADCs and molecular glue degraders. By utilizing antibodies for precise delivery and MGDs as payloads, DACs expand the therapeutic reach of ADCs into targeting intracellular protein degradation. This opens new possibilities for diseases like oncology and immune disorders (Poudel et al., J. Med. Chem., 2024; doi: 10.1021/acs.jmedchem.4c01289).
• Alternative Conjugates: Innovations like peptide-drug conjugates (PDCs) and bispecific ADCs offer smaller sizes for deeper tumor penetration or the ability to target multiple antigens.
• Click Chemistry: Advanced conjugation methods improve payload attachment stability and streamline manufacturing.

Industry Momentum and Recent Developments – ADCs are driving a wave of high-value investments and partnerships:

• Major Acquisitions: Pfizer acquired Seagen for $43 billion in 2023, while AbbVie purchased ImmunoGen for $10.1 billion, reflecting the growing demand for ADCs. In 2024, Johnson & Johnson acquired Ambrx Biopharma for $2 billion, securing advanced ADC platforms and a strong oncology pipeline.
• Innovative Partnerships: Merck & Co. licensed three ADCs from Daiichi Sankyo for $4 billion upfront in 2023, targeting a range of cancers. In 2024, Merck continued its investment with a $10 million deal with C4 Therapeutics to develop DACs, and Bristol Myers Squibb entered a $100 million agreement with Orum Therapeutics for protein degrader payloads.
• Significant Licensing Deals: Roche partnered with MediLink Therapeutics in 2024 through a $50 million upfront deal to access novel ADC candidates and linker technologies.
• Technological Advances: Eli Lilly acquired Mablink Bioscience in 2024, adding PSARlinkTM, an innovative hydrophilic linker using a polysarcosine arm, to its portfolio, which enhances ADC design by improving payload delivery and reducing off-target effects. Similarly, Sotio Biotech licensed ADC technology from Synaffix in a deal worth up to $740 million to develop solid-tumor ADCs, leveraging advanced linker systems to increase therapeutic efficacy and minimize adverse reactions.

These developments underscore the increasing importance of ADCs as a cornerstone of precision oncology and beyond.

Challenges and Future Opportunities – Despite their promise, ADCs face several challenges:

• Manufacturing Complexity: Producing ADCs requires expertise in biologics and small-molecule
  chemistry, increasing costs.
• Resistance Mechanisms: Tumor heterogeneity and resistance to payloads or targets demand novel designs and new therapeutic strategies. Resistance can also arise from antigen loss, changes in the tumor microenvironment (TME), trafficking alterations, and lysosomal mechanisms that degrade or render the ADC payload ineffective.
• Toxicity: Off-target effects remain a concern, though advancements in linker stability are mitigating these risks.

Emerging trends and opportunities include:

Overcoming ADC Resistance – To tackle resistance, next-generation ADCs are incorporating innovative solutions:

• Bispecific ADCs: These target two distinct antigens, reducing the chance of resistance through antigen escape.
• Non-internalizing ADCs: Designed to target extracellular antigens or stromal cells, bypassing inter nalization requirements.
• Advanced Payloads: Incorporating dual cytotoxic mechanisms or enhanced potency to counteract efflux pump resistance.
• Improved Linkers: Cleavable and hydrophilic linkers improve payload stability and release efficiency.

Combination Therapies – ADCs are increasingly tested alongside immunotherapies like checkpoint inhibitors and CAR-T cells, offering synergistic benefits and expanding their role in earlier treatment lines:

• Checkpoint Inhibitors: Enhance tumor-specific immune responses.
• Tyrosine Kinase Inhibitors (TKIs): Reduce survival pathway activation and efflux pump expression.
• PARP Inhibitors: Create synthetic lethality with ADCs by blocking DNA repair mechanisms.
• Predictive Biomarkers: The development of predictive biomarkers can help identify patients more likely to benefit from ADC therapy, such as those with specific gene expression profiles or resistance markers.
• Economic Incentives: Longer exclusivity periods under U.S. laws like the Inflation Reduction Act encourage investment in ADCs over small molecules.
• Sustainability Initiatives: Efforts are being made to optimize production, minimize environmental impact, and adopt greener alternatives in large-scale manufacturing. For instance, Mablink’s polysarcosine-based linker technology integrates sustainable practices, cutting chemical waste and enhancing efficiency in ADC synthesis.

Antibody-drug conjugates represent a major advance in targeted therapy, reshaping oncology and paving the way for broader applications. With continuous innovations in payloads, linkers, and delivery mechanisms, ADCs are becoming a cornerstone of precision medicine. Key advancements include linker stability improvements, which enhance drug release timing and reduce off-target effects, and the development of novel payloads like protein degraders and degrader- antibody conjugates that expand ADC efficacy into new therapeutic areas.

The integration of DACs highlights the convergence of precision targeting and dynamic protein degradation mechanisms, paving the way for next-generation therapies. Additionally, addressing resistance mechanisms through bispecific ADCs, combination therapies, and predictive biomarkers ensures ADCs remain effective against evolving tumor biology.

The global ADC market, valued at $9.4 billion in 2023, is poised for substantial growth, projected to reach $23.2 billion by 2030 with a CAGR of 13.8%. With new entrants driving innovation, ADCs are set to transform treatment paradigms, offering safer, more effective, and increasingly personalized therapies across a diverse range of diseases.

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Author: Dr. Jean Chatellier, PhD
Partner, EVP & Managing Director
KYBORA
Email: jean@kybora.com