Antibody drug conjugates beyond cytotoxic payloads

Area of Science:

• Biochemistry
• Pharmacology
• Medicinal Chemistry

Background:

• Antibody drug conjugates (ADCs) have evolved significantly, with over a dozen approved for cancer treatment.
• Brentuximab vedotin established a successful ADC template involving lysosomal payload release and specific conjugation methods.
• The field is expanding beyond cytotoxic payloads to include non-cytotoxic compounds derived from medicinal chemistry programs.

Purpose of the Study:

• To review novel ADC approaches and the medicinal chemistry origins of new non-cytotoxic payloads.
• To highlight the expansion of ADC payload diversity into non-cytotoxic classes.
• To discuss the exploration of these payloads in both oncology and non-oncology therapeutic areas.

Main Methods:

• Review of existing literature and clinical approvals of ADCs.
• Analysis of medicinal chemistry strategies for developing new ADC payloads.
• Examination of payload classes, linker technologies, and conjugation methods.

Main Results:

• ADCs have transitioned from primarily cytotoxic payloads to a broader range of compounds.
• New payload classes, originating from small molecule drug discovery, offer valuable starting points for ADC development.
• Glucocorticoid receptor modulators (GRMs) represent a clinically advanced non-cytotoxic payload class, now being explored in oncology.

Conclusions:

• The evolution of ADC payloads broadens their therapeutic applicability beyond traditional cytotoxic agents.
• Medicinal chemistry insights are crucial for designing effective non-cytotoxic payloads and linkers.
• The cross-disciplinary application of novel payloads, like GRMs, signifies a maturing and expanding field of targeted therapy.