Antibody-Drug Conjugates in Oncology

New Frontiers in Chemical Biology Enabling Drug Discovery 

Fc functions, and above all needs to target a tumor-associated antigen that is expressed in sufficient quantities on target cells, to be internalized, and to be targeted to cancer cells without any significant toxidties arising from antigen expression on normal cells. 

The conjugation chemistry employed provides the main source of variability for most conjugates. The actual sites of modification can vary from one molecule of antibody to another, and the number of sites modified for each antibody can as well. Indeed, for conjugated species with identical loading, there is still the real possibility of a complex mixture being present, as the sites of modification can still vary and this may affect all the physical and even chemical properties in different ways. 

The linker used to attach the antibody and cytotoxic agent was greatly under-appreciated in early ADC research, but has become a central focus for more recent conjugate research efforts. The broadest activity for ADCs has been obtained with cleavable linkers that contain disulfides, peptides, or acyl hydrazones that, when properly chosen, all have acceptable stability in circulation but are successfully cleaved under conditions encountered intra-cellularly. The peptides and hydrazones are most likely cleaved in the lysosomes while most disulfides are believed to be reduced in the cytosol. This approach has the additional advantage that the species released can be predicted, controlled, and modified, albeit within the limits of the linker technology. All of these approaches can be used in a self-immolative mode that cleaves off any residual linker to release a specific desired derivative in un-derivatized form.  

All of the principles described above have been explored with the conjugates described in the chapter. However, many of the conjugates in clinical trials do not contain all of the possible optimizations, e.g. they contain earlier versions of linkers that do not appear to be optimal. With the interactions between the various factors that go into the design of ADC, it will take several generations of conjugates to understand and optimize all of them. 

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