Antibody drug conjugates (ADCs) are composed of a cytotoxic payload that is attached through a linker to an antibody that selectively targets antigens on the surface of cancer cells.  ADCs can bind to and kill antigen positive cancer cells and, in some cases, release cytotoxic catabolites that can kill proximal cells in a tumor, a mechanism termed bystander killing.  Because of their tumor selectivity, ADCs have the potential to more effectively kill cells in a tumor, at tolerable doses, than conventional chemotherapeutics.  However, ADCs will not bind to cells in a tumor mass that do not express the targeted antigen, including antigen negative cancer cells and stromal cells, many of which reportedly aid cancer cells to survive and metastasis.  ADCs also have less access to tumor cells that are more distant from blood vessels.  Bystander killing allows an ADC to more efficiently kill cells that the intact conjugate cannot access.   The design of a new type of peptide-linked maytansinoid-ADC that upon cleavage of the peptide linker efficiently releases membrane permeable cytotoxic maytansinoid metabolites will be presented. The effect of altering parameters such as peptide length and stereochemistry on efficacy and tolerability will be discussed, as well as how altering the hydrophobicity of the ADC’s released catabolites effects bystander killing.  Finally, preclinical in vitro and in vivo data will be presented on the degree of bystander killing, efficacy, tolerability and pharmacokinetics in mice of these new ADCs compared to previous types of maytansinoid conjugates.

Antibody-drug conjugates: Achieving high bystander killing and improved anti-tumor activity through linker design

256th National Meeting (2018)

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