Pinatuzumab vedotin

Antibody-drug conjugates (ADCs) have advanced as a mainstay among the most promising cancer therapeutics, offering enhanced antigen targeting and encompassing wide diversity in their linker and payload components. Small-molecule inhibitors of tubulin polymerization have found success as payloads in FDA approved ADCs and represent further promise in next-generation, pre-clinical and developmental ADCs. Unique dual-mechanism payloads (previously designed and synthesized in our laboratories) function as both potent antiproliferative agents and promising vascular disrupting agents capable of imparting selective and effective damage to tumor-associated microvessels. These payloads have been incorporated into a variety of drug-linker constructs utilizing the clinically relevant cathepsin B cleavable Val-Cit dipeptide linker, employed within several FDA approved ADCs, along with other non-cleavable constructs. Various synthetic strategies were evaluated to prepare these drug-linker constructs. Aniline-based payloads were incorporated utilizing the Val-Cit dipeptide linker similar to FDA approved ADCs such as Adcetris^® (brentuximab vedotin). An additional self-immolative group, previously described in the literature for related model systems, was employed to tether the phenolic payloads. A variety of drug-linker constructs (with each bearing a unique dual mechanism payload) were synthesized and evaluated biologically for their enzyme-mediated release of payload and inhibition of tubulin polymerization. Following deactivation of the highly electrophilic maleimido terminus as its corresponding N-acetyl cysteine (NAC) derivative, the most promising construct (NAC-4) demonstrated approximately 90% release of an aniline-functionalized payload (1) upon treatment with cathepsins B or L over 90 minutes. Building on these promising results, future studies will examine the conjugation of drug-linker construct 4 to selected antibodies and engineered proteins and evaluate the biological activity of the resultant antibody-drug conjugates (ADCs).

Prostate stem cell antigen (PSCA) is expressed in all stages of prostate cancer, including in advanced androgen-independent tumors and bone metastasis. PSCA may associate with prostate carcinogenesis and lineage plasticity in prostate cancer. PSCA is also a promising theranostic marker for a variety of other solid tumors, including pancreatic adenocarcinoma and renal cell carcinoma. Here, we identified a novel fully human PSCA antibody using phage display methodology. The structure-based affinity maturation yielded a high-affinity binder, F12, which is highly specific and does not bind to 6,000 human membrane proteins based on a membrane proteome array assay. F12 targets PSCA amino acids 63-69 as tested by the peptide scanning microarray, and it cross-reacts with the murine PSCA. IgG1 F12 efficiently internalizes into PSCA-expressing tumor cells. The antimitotic reagent monomethyl auristatin E (MMAE)-conjugated IgG1 F12 (ADC, F12-MMAE) exhibits dose-dependent efficacy and specificity in a human prostate cancer PC-3-PSCA xenograft NSG mouse model. This is a first reported ADC based on a fully human PSCA antibody and MMAE that is characterized in a xenograft murine model, which warrants further optimizations and investigations in additional preclinical tumor models, including prostate and other solid tumors.