Antibody Drug Conjugate

Antibody–drug conjugates (ADCs) constitute a class of targeted biotherapeutics that combine the specificity of monoclonal antibodies with the potency of cytotoxic small molecules. The ADC platform aims to increase therapeutic index by selectively delivering a cytotoxic payload to antigen-expressing cells, thereby minimizing off-target effects relative to conventional chemotherapy.

Composition and Technical Content

An ADC is structurally composed of three critical elements:

• Monoclonal Antibody (mAb):
  • Selection Criteria: The antibody is chosen for high affinity and specificity toward a tumor-associated antigen, with minimal expression in normal tissues.
• Cytotoxic Payload:
  • Properties: Payloads are highly potent small-molecule drugs that generally exhibit sub-nanomolar activity. Common classes include auristatins (e.g., monomethyl auristatin E, MMAE), maytansinoids (e.g., DM1), and pyrrolobenzodiazepine (PBD) dimers.
• Linker Chemistry:
  • Design Criteria: The linker must be chemically stable in systemic circulation yet cleavable under specific intracellular conditions. Cleavable linkers may be pH-sensitive, enzyme-sensitive, or reducible via disulfide bonds. Non-cleavable linkers rely on complete proteolytic degradation of the antibody to release the active drug.

Applications

• Oncology: ADCs are primarily applied in cancer treatment. They offer targeted delivery of cytotoxic agents to tumor cells while sparing normal tissues, thus reducing systemic toxicity. 
• Therapeutic Window: The optimization of ADCs involves balancing stability in circulation, efficient internalization, and effective payload release to maximize the therapeutic window.
• Clinical Development and Challenges: Ongoing research focuses on enhancing ADC stability, improving site-specific conjugation techniques, designing novel payloads with different mechanisms of action, and identifying new tumor-associated antigens. 

ADCs represent a convergence of immunology, chemistry, and pharmacology to deliver potent cytotoxic agents selectively to diseased cells. Their design relies on precise engineering of antibodies, linkers, and payloads, forming a sophisticated yet focused therapeutic modality that aims to improve cancer treatment outcomes with reduced systemic side effects.