VALIDATION OF HPTM-001, A HUMANIZED CANDIDATE THERAPEUTIC ANTIBODY FOR PROMOTING MUCOSAL WOUND HEALING IN IBD

Abstract

Abstract A hallmark of the clinical course of patients with Inflammatory Bowel Disease (IBD) is poorly healing erosions and ulcers in the intestinal mucosa. Despite the adverse clinical consequences of non-healing mucosal wounds in IBD, current front-line therapies that selectively target mucosal wound healing are not available. Recent studies revealed an association between colonic inflammation and aberrant glycosylation of epithelial CD44v6. Under conditions of inflammation, epithelial CD44v6 was shown to be decorated with the terminal glycan sialyl Lewis A. Importantly, targeting sialylated Lewis glycans on CD44v6 with a murine antibody GM35 was shown to promote mucosal wound healing in cell lines and in biopsy based wounding assays as well as dextran sodium sulfate (DSS) induced murine colitis models. We sequenced CDRs from GM35 and produced a humanized antibody. Eight candidate human IgG1 clones were produced and screened. hPTM-001.4772 was selected from the eight candidates based on glycan affinity and selectivity compared to GM35. In vitro wound healing studies revealed that PTM-001.4772 was as effective as GM35 in promoting repair of scratch wounds with human intestinal epithelial cells. Furthermore, intraperitoneal injection of mice with hPTM-001.4772 during induction of DSS colitis resulted in reduced weight loss compared to control IgG. These results suggest that hPTM-001.4772 is well-positioned as a unique potential candidate therapeutic for IBD that can be used to selectively promote healing of mucosal wounds and ulcers.