To target CLDN18.2 – a membrane protein expressed in many gastric and pancreatic adenocarcinomas, but normally only in the epithelium of the stomach – Zhu et al. generated an anti-CLDN18.2 antibody-drug (auristatin) conjugate (ADC) and CD3-bispecific or diabody formatted molecules. All three therapies killed tumor cell lines that expressed human CLDN18.2 in vitro. In patient-derived xenograft mouse models of gastric and pancreatic cancers, all treatments exhibited a dose-dependent antitumor effect, with ADC slowing tumor growth, and bispecific and diabody molecules inducing tumor regressions. Treatments were well tolerated.
Human CLDN18.2 is highly expressed in a significant proportion of gastric and pancreatic adenocarcinomas, while normal tissue expression is limited to the epithelium of the stomach. The restricted expression makes it a potential drug target for the treatment of gastric and pancreatic adenocarcinoma, as evidenced by efforts to target CLDN18.2 via naked antibody and CAR-T modalities. Herein we describe CLDN18.2-targeting via a CD3-bispecific and an antibody drug conjugate and the characterization of these potential therapeutic molecules in efficacy and preliminary toxicity studies. Anti-hCLDN18.2 ADC, CD3-bispecific and diabody, targeting a protein sequence conserved in rat, mouse and monkey, exhibited in vitro cytotoxicity in BxPC3/hCLDN18.2 (IC50 = 1.52, 2.03, and 0.86 nM) and KATO-III/hCLDN18.2 (IC50 = 1.60, 0.71, and 0.07 nM) respectively and inhibited tumor growth of pancreatic and gastric patient-derived xenograft tumors. In a rat exploratory toxicity study, the ADC was tolerated up to 10 mg/kg. In a preliminary assessment of tolerability, the anti-CLDN18.2 diabody (0.34 mg/kg) did not produce obvious signs of toxicity in the stomach of NSG mice 4 weeks after dosing. Taken together, our data indicate that targeting CLDN18.2 with an ADC or bispecific modality could be a valid therapeutic approach for the treatment of gastric and pancreatic cancer.
Author Info: (1) Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA. gzhu108@live.com. (2) Pfizer Cancer Imm
Author Info: (1) Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA. gzhu108@live.com. (2) Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA. 23 and Me, 349 Oyster Point Blvd, South San Francisco, CA, 94080, USA. (3) Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA. (4) Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA. Gilead Sciences, 333 Lakeside Drive, Foster City, CA, 94404, USA. (5) Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA. Grifols Diagnostic Solutions, 6455 Christie Ave B-334C, Emeryville, CA, 94608, USA. (6) Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA. Kodiak Sciences Inc., 2631 Hanover St, Palo Alto, CA, 94304, USA. (7) Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA. Applied Molecular Transport, 1 Tower Place, Suite 850, South San Francisco, CA, 94080, USA. (8) Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA. Grifols Diagnostic Solutions, 6455 Christie Ave B-334C, Emeryville, CA, 94608, USA. (9) Drug Safety Research and Development, Pfizer Worldwide Research and Development, 10646 Science Center Dr., San Diego, CA, 92121, USA. Covance Inc. Early Phase Development Solutions, 3301 Kinsman Blvd, Madison, WI, 53704, USA. (10) Drug Safety Research and Development, Pfizer Worldwide Research and Development, 10646 Science Center Dr., San Diego, CA, 92121, USA. (11) BioMedicine Design, Pfizer Worldwide Research and Development, 10646 Science Center Dr., San Diego, CA, 92121, USA. (12) Drug Safety Research and Development, Pfizer Worldwide Research and Development, 10646 Science Center Dr., San Diego, CA, 92121, USA. (13) Drug Safety Research and Development, Pfizer Worldwide Research and Development, 280 Shennecossett Rd, Groton, CT, 06340, USA. GSK, 1250 South Collegeville Road, Collegeville, PA, 19426, USA. (14) Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA. Alector, 151 Oyster Point Blvd #300, South San Francisco, CA, 94080, USA. (15) Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA. (16) Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA. (17) Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA. (18) Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA. Allogene Therapeutics, 210 E. Grand Avenue, South San Francisco, CA, 94080, USA. (19) Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA. Bristol-Myers Squibb, 700 Bay Rd suite A, Redwood City, CA, 94063, USA. (20) Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA. (21) Pfizer Cancer Immunology Discovery, Pfizer Worldwide Research and Development, 230 E. Grand Avenue, South San Francisco, CA, 94080, USA. Multitude Therapeutics, Abmart, 3698 Haven Avenue Suite A, Redwood City, CA, 94063, USA.
