Chiu-Chen Huang

A novel apoptosis-inducing anti-PSGL-1 antibody for T cell-mediated diseases

We previously discovered a hamster monoclonal antibody, TAB4, against mouse PSGL‐1/CD162 that can induce death of activated T cells. Here, we further investigated the potential of TAB4 in treating two murine models of T cell‐mediated diseases. The results showed that administration of TAB4 suppressed incidence and severity of both GVHD and type I diabetes. Analyses of apoptotic T cells ex vivo shortly after antibody injection revealed a higher percentage of apoptosis among activated T cells in the TAB4‐treated group than in the control group. Furthermore, restoration of functional donor T cells was observed in TAB4‐treated mice. As TAB4 does not affect the binding of P‐selectin to activated T cells, our data suggest that its long‐lasting therapeutic effect on inhibiting disease progression is attained by specifically inducing apoptosis of activated T cells. These data hence extend our previous finding of the novel property of PSGL‐1 and strongly indicate that the PSGL‐1‐specific apoptosis‐inducing antibody is a new therapeutic agent possessing a great potential for controlling GVHD and other T cell‐mediated autoimmune diseases.

Abstract 2517: Potent antitumor activity of AbGn-ADC, a humanized monoclonal antibody conjugated with dolastatin analogue, to gastric and pancreatic cancers expressing AbGn carbohydrate epitope

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL AbGn is a glycotope-specific humanized monoclonal antibody recognizing Lewisa- like carbohydrate expressed in gastric and pancreatic cancer cells. While AbGn binding to normal tissues is restricted to only luminal surface of the epithelium in gastro-intestinal track and secretory glands, about 50% of gastric and pancreatic cancer samples tested express AbGn epitope and can be recognized by AbGn antibody. FACS analysis and confocal microscopic studies demonstrated extensive internalization of AbGn after binding to the cell surface. The internalized AbGn co-localized with lysosomal marker LAMP1, suggesting that AbGn-mediated internalization followed the lysosomal pathway. A novel antibody-drug conjugate (AbGn-ADC) was generated by linking AbGn to a dolastatin analogue, a potent inhibitor of microtubulin polymerization, through a dipeptide-based cleavable linker. This AbGn-ADC was evaluated for antitumor activity in vitro and in mouse xenograft models. AbGn-ADC eliminated cancer cell lines with nanomolar potency in vitro. No cell death could be detected in SW480 cells, a gastric cell line with no AbGn epitope expression, suggesting high selectivity of AbGn-ADC. When used to treat mice with established human gastric (SNU-16) or pancreatic (Panc.02.03B) cancer xenografts, AbGn-ADC significantly reduced the size of the established tumors (p<0.01). No body weight loss or signs of toxicity was observed in AbGn-ADC treated mice. These findings support the potential of further development of AbGn-ADC for treating gastric and pancreatic cancers. Data from pre-clinical AbGn-ADC tolerability study in relevant non-human primate will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2517. doi:1538-7445.AM2012-2517