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Degrader–antibody conjugates (DACs), including PROTAC- and molecular glue–based platforms, represent a paradigm shift beyond traditional cytotoxic antibody-drug conjugates (ADCs) in oncology. By leveraging antibody-mediated targeting with selective protein degradation, DACs promise both efficacy and specificity. However, these innovative modalities introduce a distinct and complex safety profile that requires careful consideration.

Traditional antibody-drug conjugates (ADCs) have delivered cytotoxic payloads—often tubulin or topoisomerase inhibitors—directly to antigen-positive tumor cells, providing targeted cell killing while limiting off-target effects. However, the emergence of degrader–antibody conjugates (DACs), particularly those based on proteolysis-targeting chimeras (PROTACs) and molecular glues, has introduced a new therapeutic strategy: harnessing targeted protein degradation rather than inhibition.

Antibody–drug conjugates (ADCs) are a rapidly evolving class of targeted chemotherapeutics that combine the tumor selectivity of monoclonal antibodies (mAbs) with the potent cytotoxicity of small-molecule payloads. Through rational linker design and optimized bioconjugation, ADCs have steadily advanced toward the goal of precision cancer therapy, achieving enhanced efficacy and reduced off-target toxicity. As of 2026, more than 15 ADCs have been approved globally for hematologic and solid tumors, with over 2,000 candidates in development and worldwide sales projected to exceed $16 billion

Mitigating Developability and Manufacturing Risks for Novel ADCs

Antibody–drug conjugates (ADCs) have transformed targeted cancer therapy by enabling the selective delivery of cytotoxic agents to tumor cells, sparing healthy tissue. The design of ADCs allows for higher doses of the cytotoxic drug to be administered, potentially increasing efficacy. They are currently considered the most promising drug classes in oncology, with ongoing efforts to expand their use for non-oncological indications and in combination therapies.

Antibody-drug conjugates (ADCs) have emerged as a transformative class of targeted cancer therapeutics, combining the specificity of monoclonal antibodies with the cytotoxicity of potent payloads. The development of NBE-002*, an ROR1-targeted ADC using the highly potent anthracycline derivative PNU-159682, provides valuable insights into the opportunities and challenges of ADC chemical design. By examining the story of NBE-002, we can better understand how payload potency, linker chemistry, and conjugation strategy determine both preclinical promise and clinical limitations.

TROP-2 and the Promise and Peril of High-Affinity in ADCs -- Over the last decades, Antibody–drug conjugates (ADCs) have emerged as a transformative class of cancer therapeutics, offering the promise of targeted cytotoxicity with the precision of monoclonal antibodies.* To fulfill this promise, the ideal ADC includes an antibody that is specific for binding to the target antigen, has high binding affinity for that target, and, at the same time, has low immunogenicity.  In addition, the antibody should have a long plasma half-life and rapid internalization.

Antibody-Drug Conjugates in Oncology: Why Potency Is No Longer the Limiting Factor

The Most Interesting Activity in ADC Development is no Longer Happening in Traditional Formats

TUB-040: A Next-Generation NaPi2b-Targeted ADC for Ovarian and Lung Cancer