Abstract 1069: OBT076, a clinical-stage ADC, displays synergy with oxaliplatin and cisplatin in preclinical gastric cancer models

Abstract

Abstract CD205 is a transmembrane glycoprotein, robustly expressed in malignancies from varied histotypes, making it an ideal target for Antibody Drug Conjugate (ADC) therapy. OBT076 is a novel and selective clinical stage ADC with potent activity against CD205-positive liquid and solid tumors. We explored the cellular cytotoxicity profile of combination chemotherapy with OBT076 and two standard-of-care platinum-based compounds, Oxaliplatin (Ox) and Cisplatin (Cis), in preclinical gastric, pancreatic and colorectal cancer models. A panel of gastric cancer and other solid tumor cell lines were selected, based on mRNA data, for CD205 expression. This was confirmed using flow cytometry. The cell lines were assessed for susceptibility to monotherapy with OBT076, Ox and Cis. Cells lines displaying positive cytotoxic responses were assessed for susceptibility to combination chemotherapy by first treating cells with a single dose of OBT076 for 72 hours, leading to 20% growth inhibition (IC20), and subsequently with either Ox or Cis for 48 hours (OBT-Ox and OBT-CIS, respectively). The ATP-dependent fluorescence-based cellular viability system cell titer-glo was used as the cytotoxic readout. In our preclinical gastric cancer model, pre-treatment with OBT076 followed by either Ox or Cis displayed synergistic combination effects, reducing the half-maximal inhibitory concentration (IC50) of Ox and Cis by 40- and 10-fold respectively. The resultant cellular cytotoxicity of OBT-Ox and OBT-Cis combination therapy was higher compared to monotherapy with either agent. Moreover, while monotherapy with Ox was less potent than with Cis, OBT-Ox achieved similar potency to OBT076-Cis. For colorectal and pancreatic cancer models, the effects were less pronounced: OBT076-combination therapy increased Platinum sensitivity by 2 to 5 times. No synergistic effects were observed when the treatment order was reversed. These results and those from ongoing in vivo studies in gastric cancer models will be discussed. In summary OBT076, a clinical stage ADC displays synergistic anti-tumor effects in preclinical gastric cancer models, when used in combination with Ox or Cis. OBT076 is currently being evaluated in the gastric clinical population where Platinum-based therapies remain the mainstay of treatment. Citation Format: Arnima Bisht, Murray Cox, Chander Sekhar Peddaboina, Michael Crocamo, Abderrahim Fandi, Christian Rohlff. OBT076, a clinical-stage ADC, displays synergy with oxaliplatin and cisplatin in preclinical gastric cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1069.