2. Academic Validation
  3. A Novel, Fully Human Anti-fucosyl-GM1 Antibody Demonstrates Potent In Vitro and In Vivo Antitumor Activity in Preclinical Models of Small Cell Lung Cancer

A Novel, Fully Human Anti-fucosyl-GM1 Antibody Demonstrates Potent In Vitro and In Vivo Antitumor Activity in Preclinical Models of Small Cell Lung Cancer

  • Clin Cancer Res. 2018 Oct 15;24(20):5178-5189. doi: 10.1158/1078-0432.CCR-18-0018.
Paul Ponath 1,  Daniel Menezes 1,  Chin Pan 1,  Bing Chen 1,  Miho Oyasu 1,  Debbie Strachan 1,  Heidi LeBlanc 1,  Huadong Sun 2,  Xi-Tao Wang 2,  Vangipuram S Rangan 1,  Shrikant Deshpande 1,  Sandra Cristea 3,  Kwon-Sik Park 3,  Julien Sage 3,  Pina M Cardarelli 4
Affiliations

Affiliations

  • 1 Biologics Discovery California, Bristol-Myers Squibb, Redwood City, California.
  • 2 Bristol-Myers Squibb, Princeton, New Jersey.
  • 3 Departments of Pediatrics and Genetics, Stanford University School of Medicine, Stanford, California.
  • 4 Biologics Discovery California, Bristol-Myers Squibb, Redwood City, California. [email protected].
PMID: 30021910 DOI: 10.1158/1078-0432.CCR-18-0018
Abstract

Purpose: The ganglioside fucosyl-GM1 (FucGM1) is a tumor-associated antigen expressed in a large percentage of human small cell lung Cancer (SCLC) tumors, but absent in most normal adult tissues, making it a promising target in immuno-oncology. This study was undertaken to evaluate the preclinical efficacy of BMS-986012, a novel, nonfucosylated, fully human IgG1 antibody that binds specifically to FucGM1.Experimental Design: The antitumor activity of BMS-986012 was evaluated in in vitro assays using SCLC cells and in mouse xenograft and syngeneic tumor models, with and without chemotherapeutic agents and checkpoint inhibitors.Results: BMS-986012 showed a high binding affinity for FcγRIIIa (CD16), which resulted in enhanced antibody-dependent cellular cytotoxicity (ADCC) against FucGM1-expressing tumor cell lines. BMS-986012-mediated tumor cell killing was also observed in complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP) assays. In several mouse SCLC models, BMS-986012 demonstrated efficacy and was well tolerated. In the DMS79 xenograft model, tumor regression was achieved with BMS-986012 doses of 0.3 mg/kg and greater; antitumor activity was enhanced when BMS-986012 was combined with standard-of-care cisplatin or etoposide. In a syngeneic model, tumors derived from a genetically engineered model of SCLC were treated with BMS-986012 or anti-FucGM1 with a mouse IgG2A Fc and their responses evaluated; when BMS-986012 was combined with anti-PD-1 or anti-CD137 antibody, therapeutic responses significantly improved.Conclusions: Single-agent BMS-986012 demonstrated robust antitumor activity, with the addition of chemotherapeutic or immunomodulatory agents further inhibiting SCLC growth in the same models. These preclinical data supported evaluation of BMS-986012 in a phase I clinical trial of patients with relapsed, refractory SCLC. Clin Cancer Res; 24(20); 5178-89. ©2018 AACR.

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