The new wave of cancer therapy

Antibody Drug Conjugates

Today let's talk about the new wave of cancer therapy typically ADCs also known as Antibody drug conjugates. The idea of this class of drugs was initiated with Paul Ehrlich who started the wave of cytotoxic chemotherapy and who also pointed to the future of antibodies as "Magic Bullets".
Naked antibodies have great specificity to cancer cells but, as single agents, often have limited anti-tumor activity, particularly against solid tumors.
Chemotherapy which alone often suffers from lack of tumor specificity but it has shown a clinical effect. Thus the combination of this two classes of drugs gives us what we call Antibody drug conjugates.

ADCs or Antibody–drug conjugates is the combination of cytotoxic drugs and monoclonal antibodies via a linker. This ADCs are directed to antigens over expressed in tumor cells.
These loaded antibodies are expected to selectively deliver cytotoxic agents to tumor cells and provide sustained clinical benefit to pre-selected cancer patients while, at the same time, minimizing systemic toxicity.

This image shows us the structure of the Antibody drug conjugate which is composed from :

• antibody
• cytotoxic agent
• linker

Monoclonal antibodies are laboratory-produced molecules engineered to deliver cytotoxic agents to cancer cells. They
are designed to bind to antigens that are expressed in the surface of tumor cells.

• the target antigen should be highly expressed on tumor cells with limited expression on healthy tissues to avoid the destruction of healthy cells.
• Antibody also should have high affinity and avidity for tumor antigen to have a good binding between the antibody and the antigen

The linker connects the cytotoxic payload to the monoclonal antibody and maintains the antibody–drug conjugate in a fairly stable state in circulation. Linkers react with lysine sidechains on the antibody or with sulfhydryl groups in the hinge regions of the antibody.
Most linkers are labile in the intracellular environment, resulting in the release of
the cytotoxic payload after internalization.

• acid-labile hydrazones are degraded in the lysosome under low pH conditions.
• disulphide linkers are cleaved selectively in the reductive cytosolic cellular milieu
• Thioether linkers depend on degradation of the antibody in the lysosome for release of the cytotoxic payload.

Cytotoxic agents are toxic to cancer cells. They kill cancer cells or stop them from multiplying. These fall into two main mechanistic classes :
The first are tubulin inhibitors, which act on dividing cells by binding to tubulin, thereby inhibiting polymerization, resulting in cell cycle arrest and apoptosis. The other main mechanistic class of drugs used as ADC warheads are agents that target cellular DNA

Mode of action of ADCs

As you can see the mode of action of antibody drug conjugates start with the binding between the antibody and the antigen, then the ADC–antigen complex is internalized into the cell through receptor-mediated endocytosis. the degradation of the endosome which is a membrane-bound compartment by the lysosome releases the cytotoxic agent either by direct cleavage of the linker or by proteolysis of the antibody.

BRENTUXIMAB VEDOTIN

Brentuximab vedotin is an antibody drug conjugate that treats Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL). it selectively targets the CD30 antigen expressed in cancer cells.

In this image you can see that after the internalization of the ADC into the cell it releases a cytotoxic agent which is MMAE, MMAE interact with the tubulin resulting in cell death.

Conclusion

The field is rapidly expanding, with over 20 ADCs currently in clinical trials and many more in preclinical development.
ADCs continue to be optimized for clinical use by careful consideration of the appropriate tumor target, and by exploiting innovations in antibody engineering, conjugation chemistry, linker technology, and design of the cytotoxic warhead.