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Development of A Novel RON Targeted Antibody‐Drug Conjugates using Cysteine Bridging Technology for Potential Treatment of Pancreatic Cancer
Author(s) -
suthe sreedhar reddy,
Yao HangPing,
trippier paul c.,
wang minghai
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.807.7
Subject(s) - pancreatic cancer , cancer research , medicine , antibody drug conjugate , conjugate , therapeutic index , antibody , drug , pharmacology , cancer , monoclonal antibody , immunology , mathematical analysis , mathematics
Therapeutics targeting known oncoproteins have been applied for pancreatic cancer treatment but clinical outcomes are not promising. Hence, there is an urgent need to identify novel targets and develop effective drugs to improve pancreatic cancer therapeutic index. Antibody‐drug conjugates (ADC) represent a promising class of drugs for targeted cancer therapy. Here we developed a novel ADC targeting RON receptor tyrosine kinase for potential pancreatic cancer treatment. To this end, we have synthesized a bis‐alkylating linker (BL), attached to a lysosomal protease‐cleavable dipeptide with payload Monomethyl auristatin E (MMAE). The BL‐MMAE was then conjugated to Zt/g4 (anti‐RON mAb) through cysteine bridging technology to produce Zt/g4‐BL‐MMAE with a relatively homogeneous conjugation profile and an antibody to drug ratio of 1:4. Zt/g4‐BL‐MMAE showed significant improvement in drug conjugation homogeneity and serum stability over conventional ADCs prepared by maleimide‐based linkers. In pancreatic cancer cell lines overexpressing RON, Zt/g4‐BL‐MMAE specifically targeted RON‐expressing tumor cells and was effective in rapid induction of cell surface RON endocytosis. Functional analysis revealed that Zt/g4‐BL‐MMAE caused cell cycle arrest at G2/M phase, reduction of cell viability and subsequently resulted in massive cell death. The calculated IC50 is in the range of 1 to 2 μg/ml. Therapeutic studies using mouse xenograft models are currently underway to determine the efficacy of Zt/g4‐BL‐MMAE for pancreatic and other epithelial cancers. We conclude that Zt/g4‐BL‐MMAE is a novel anti‐RON ADC with excellent conjugation profile, serum stability, and selective cytotoxicity for pancreatic cancer cells. This work provides a pharmaceutical opportunity for evaluating potentials of RON‐targeted ADCs in pancreatic cancer treatment in the future. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .