tubulysin-a and Ovarian-Neoplasms

Antibody-drug conjugates (ADCs) use antibodies to deliver cytotoxic payloads directly into tumor cells via specifically binding to the target cell surface antigens. ADCs can enhance the anti-tumor effects of antibodies, and increase the delivery of cytotoxic payloads to cancer cells with a better therapeutic index. An ADC was prepared with a potent carbamate-containing tubulysin analogue attached to an anti-mesothelin antibody via a Cit-Val dipeptide linker. An aniline functionality in the tubulysin analogue was created to provide a site of linker attachment via an amide bond that would be stable in systemic circulation. Upon ADC internalization into antigen-positive cancer cells, the Cit-Val dipeptide linker was cleaved by lysosomal proteases, and the drug was released inside the tumor cells. The naturally occurring acetate of tubulysin was modified to a carbamate to reduce acetate hydrolysis of the ADC in circulation and to increase the hydrophilicity of the drug. The ADC bearing the monoclonal anti-mesothelin antibody and the carbamate-containing tubulysin was highly potent and immunologically specific to H226 human lung carcinoma cells in vitro, and efficacious at well-tolerated doses in a mesothelin-positive OVCAR3 ovarian cancer xenograft mouse model.

Topics: Animals; Antineoplastic Agents; Carbamates; Female; GPI-Linked Proteins; Humans; Immunoconjugates; Lung Neoplasms; Mesothelin; Mice; Mice, SCID; Oligopeptides; Ovarian Neoplasms

A series of tubulysin analogs in which one of the stereogenic centers of tubuphenylalanine was eliminated were synthesized. All compounds were tested for antiproliferative activity towards ovarian cancer cells and for inhibition of tubulin polymerization. The dimethyl analogs were generally more active than the desmethyl analogs, and four analogs have tubulin polymerization IC(50) values similar to combretastatin A4 and the hemiasterlin analog HTI-286.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Female; Humans; Inhibitory Concentration 50; Models, Chemical; Oligopeptides; Ovarian Neoplasms; Phenylalanine; Stilbenes; Structure-Activity Relationship; Tubulin Modulators