Identification of an Internalizing Cancer Target for Novel Antibody Drug Conjugate Development by A&G Pharmaceutical and Precision Antibody Researchers
COLUMBIA, Maryland, February 10, 2021: Precision Antibody and A&G Pharmaceutical are pleased to announce the publication, in PLOS One, of the results of their collaborative study about the identification of Prostaglandin F2 receptor negative regulator as a cancer cell surface target and the isolation of internalizing antibody for antibody drug conjugate development.
Antibody-Drug Conjugates (ADCs) are a combination of biological and small-molecule drugs that have recently received increased interest as therapeutic choices in oncology. ADCs are composed of a monoclonal antibody (mAb), which specifically binds to a cell surface target, a linker, and a cytotoxic payload. After binding to its cell-surface antigen, the mAb induces endocytosis of said antigen, shuttling the toxic payload inside the cell. Several ADCs have been approved by the Food and Drug Administration (FDA) as treatment for hematopoietic and solid tumors. For example, Kadcyla, or T-DM1 is an ADC consisting of the anti-HER2 mAb Trastuzumab conjugated to emtansine via a non-reducible thioether linker. Kadcyla is approved to treat HER-2 overexpressing breast cancer patients and is reported to be more potent than Trastuzumab particularly for breast cancer patients with moderate tumor Her-2 expression who would be not eligible for Trastuzumab treatment. In 2020, two additional ADCs have been FDA-approved for solid tumors: Enhertu (fam‐trastuzumab deruxtecan) and salcitruzumab-Govitacan (Trop-2 ADC) both for metastatic breast cancer. This shows the continued and increasing interest and R&D activities on developing ADCs to novel cancer targets.
The combined approach used by A&G and Precision Antibody has centered on the identification of new cell-surface targets that can be internalized and are expressed on cancer cells by screening hybridoma libraries developed against cancer cell-surface antigens. These antibody libraries are then screened for their ability to bind to specific cancer cells, internalize, and then deliver a cytotoxic payload to target cells. For unknown targets, the selected antibody is then used to identify its binding protein by proteomics approach followed by examining the therapeutic potential of the target on cancer cells. This approach was used by Precision Antibody and A&G Pharmaceutical to characterize an internalizing mouse monoclonal antibody, identify its target by mass spectrometry as PTGFRN and shows its efficacy as an ADC in vitro and in vivo, for several cancer cell lines including head and neck cancers and spindle cell carcinoma. PTGFRN is a member of a still unknown family of cell surface proteins called tetraspanins which are contributing to many key biological functions linked to adhesion, migration and survival and show promise as therapeutic targets.
“We are delighted to have identified in PTFGRN a promising internalizing cancer target that could increase the repertoire of therapeutic options for many cancers with unmet needs via developing anti-PTGFRN ADCs. After having developed diagnostic and therapeutic products for a circulating factor progranulin, it is exciting to explore new cancer therapeutic options based on a cell surface protein” declared Dr. Ginette Serrero, A&G Pharmaceutical CEO.
For Dr. Jun Hayashi, President of Precision Antibody, “knowing that Precision internalizing antibody development program is contributing to the potential launch of new targeted therapy for several cancers is rewarding”.
This study is described in the article entitled Identification of Prostaglandin F2 Receptor Negative Regulator (PTGFRN) as an internalizable target in cancer cells for antibody drug conjugate by J. Marquez et al. (2021) PLoS ONE 16 (1) 1-18.
Precision Antibody has developed a custom program for the selection of internalizing antibodies for cell surface target for maximum success. This includes a strategized antigen design and immunization program followed by targeted antibody screening including high throughput selection of internalizing antibodies, cell line identification and proof-of-concept functional assays.
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