No abstract

No abstract

Sch 34343 showed a linear dose response (with respect to AUCs) in mice following both intravenous and subcutaneous administration. It was 100% bioavailable following subcutaneous administration. Peak serum levels, AUCs, beta-phase half-life and recovery of Sch 34343 from the urine of mice indicated that it was similar to cephalothin and cefamandole. In experimental mouse infections, against Gram-negative strains, Sch 34343 was more active than cephalothin, equal to or more active than cefamandole and cefoxitin, but less active than latamoxef (moxalactam) and cefotaxime following single or multiple dose therapy. It was the most active compound against Staphylococcus. Sch 34343 was equally active against strains sensitive to beta-lactams and strains producing beta-lactamases. In an anaerobic abscess model in mice, Sch 34343 was more active than cefoxitin and clindamycin against Bacteroides fragilis. In Escherichia coli meningitis in rabbits, it cured rabbits with a single intravenous dose of 50 mg/kg.

No abstract

Treatment for patients with advanced solid tumors that include triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and castrate resistant prostate cancer (CRPC), as well as Mantle Cell Lymphoma (MCL), while increasing survival is not curative. We have identified a membrane bound protease, “activated” matriptase, as an attractive target antigen for highly selective antibody delivery of cytotoxins as activated matriptase expression is restricted to epithelial tumors and some B-cell lymphomas. We generated a novel ADC by linking M69, a mouse antibody specific to activated matriptase, to monomethyl auristatin E (MMAE) via a PEGylated, releasable di-peptide linker as a proof-of-principle prototype. Both in cell lines and in human xenograft models of TNBC, NSCLC, CRPC and MCL, the conjugate was found to exhibit potent anticancer activity against all of these tumor types without toxicity. Encouraged by these results, we are also exploring the use of this ADC against gastric and pancreatic cancer, and in combination with chemotherapy and immunotherapy. As this is a mouse antibody, we are also generating a chimeric antibody for toxicity studies in primates. Citation Format: Siang-Yo Lin, Zoltan Szekely, Chen-Yong Lin, Joseph R. Bertino, Gulam Mohmad Rather. Development of an antibody-drug conjugate with broad anticancer activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4615. doi:10.1158/1538-7445.AM2017-4615