Targeting Solid Cancers with a Cancer-Specific Monoclonal Antibody to Surface Expressed Aberrantly O-glycosylated...

Area of Science:

• Oncology
• Immunotherapy
• Glycobiology

Background:

• Current immunotherapies for solid tumors are limited by a lack of cancer-selective antibodies, as many targets are also present in healthy tissues.
• Aberrant glycosylation in solid tumors creates unique tumor-associated carbohydrate antigens, offering potential for cancer-specific targeting.
• Targeting these aberrant glycopeptide epitopes is a promising strategy for developing potent and selective immunotherapies.

Purpose of the Study:

• To identify a cancer-specific glycopeptide epitope for targeted immunotherapy.
• To develop a novel monoclonal antibody (mAb) targeting this epitope.
• To evaluate the efficacy and safety of mAb-based chimeric antigen receptor (CAR) T cells in solid tumor models.

Main Methods:

• Utilized O-glycoproteomics to identify a distinct glycopeptide epitope in CD44v6, a cancer-associated isoform.
• Developed a cancer-specific mAb (4C8) using a glycopeptide immunization strategy.
• Assessed 4C8 binding, cancer specificity via immunohistochemistry (IHC), and in vitro/in vivo efficacy of 4C8 CAR T cells.

Main Results:

• Identified and targeted a Tn-glycosylated CD44v6 epitope with the cancer-specific mAb 4C8, exhibiting low nanomolar affinity.
• Demonstrated high cancer specificity of 4C8 by IHC across various healthy and cancerous tissues.
• 4C8 CAR T cells showed specific cytotoxicity, significant tumor regression, and increased survival in vivo, with selective killing in a mixed cancer model.

Conclusions:

• Targeting the CD44v6 glycopeptide epitope with the 4C8 mAb offers a highly cancer-selective approach for immunotherapy.
• 4C8 CAR T cells demonstrate potent anti-tumor activity and favorable safety profiles, sparing healthy tissues.
• This strategy holds significant potential for advancing the treatment of solid tumors through targeted immunotherapy.