On October 31, 2023 CatalYm reported the presentation of two preclinical data sets expanding the mechanistic understanding and clinical application of its lead anti-GDF-15 antibody candidate, visugromab, at the upcoming Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 2023 Annual Meeting in San Diego, USA (Press release, Catalym, OCT 31, 2023, View Source [SID1234636593]). The findings will be presented in two poster sessions on Friday, November 3rd, and Saturday, November 4th, and provide further clarification on GDF-15-mediated inhibition of T cell infiltration and highlight the potential of combining visugromab with bispecific T-cell engagers as a novel approach in cancer therapy. Visugromab is currently evaluated in a broad Phase 2 program in combination with anti-PD-1 treatment in multiple solid tumor indications.
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"We are advancing our understanding of the underlying molecular mechanisms that are the foundation for GDF-15’s central role in tumor resistance to immunotherapy and visugromab’s potential to reinstate anti-tumor activity and enhance responses," said Dr. Christine Schuberth-Wagner, Chief Scientific Officer at CatalYm. "The new data for the combination of visugromab with bispecific T-cell engagers provide strong scientific support for a synergistic effect in this novel therapeutic setting. We will further investigate this combination, which could extend durability and improve outcomes for a broad range of cancer patients with high medical need."
Poster Presentation Identifying SHP-1 as Central Mediator of GDF-15-related T Cell Adhesion Inhibition
The first data set further expands understanding of visugromab’s mechanism of action and the underlying pathways involved in the development of GDF-15-mediated therapy resistance in cancer cells. When investigating the involvement of additional cell adhesion pathway components downstream of GDF-15, SHP-1 was identified as a central mediator of GDF-15-related inhibition of T cell adhesion. SHP-1 is an intracellular tyrosine phosphatase known as a negative regulator of antigen-dependent activation and proliferation of T cells. Inhibition of SHP-1 resulted in abrogation of GDF-15’s inhibitory effect. The researchers confirmed that GDF-15 via SHP-1 inhibits the phosphorylation of ZAP-70, another intracellular tyrosine kinase involved in LFA-1 inside-out activation and T cell receptor signaling. These data connect SHP-1 as a downstream effector to the recently published GDF-15-mediated reduction of high-affinity LFA-1 conformation, leading to impaired endothelial adhesion and transmigration of T cells toward the tumor site.
Poster Presentation Details
Title: SHP-1 is a central mediator of GDF-15 mediated adhesion inhibition in T cells
Presenter: Dr. Christine Schuberth-Wagner
Abstract number: 1049
Date and time: Friday, Nov 3rd, 5:00-6:30pm PDT
Poster Presentation on Visugromab/T-Cell Engager Combination
The second data set supports the expansion of visugromab’s application to combinations with immune cell-engaging therapies, underlining its potential to be a critical component for treatment success in a broad range of anti-cancer regimens. The preclinical analyses investigated a new combination of visugromab with a bispecific T-cell engager (tebentafusp). Anti-tumor activity of bispecific T-cell engagers is dependent on infiltration of effector T cells into the tumor microenvironment. In vivo analyses in a mouse tumor model demonstrated that the combination with visugromab significantly increased the number of intratumoral T cells compared with tebentafusp alone. This indicates a direct positive impact of visugromab’s infiltration-enhancing activity on the anti-tumor activity of bispecific T-cell engaging treatments and provides a strong rationale to further investigate this therapeutic concept.
Poster Presentation Details
Title: GDF-15 neutralizing antibody visugromab increases intratumoral immune cell infiltration to support bispecific T-cell engagers
Presenter: Dr. Christine Schuberth-Wagner
Abstract number: 1196
Date and time: Saturday, Nov 4th, 7:00-8:30pm PDT
CatalYm is investigating its GDF-15-neutralizing antibody visugromab in a broad Phase 2 clinical program, the GDFather (GDF-15 Antibody-mediaTed Human Effector Cell Relocation) trials, in combination with the anti-PD-1 inhibitor nivolumab in patients with advanced solid tumors. First interim data from the Phase 2 (NCT04725474) trial continue to demonstrate a very good safety and tolerability profile and promising early responses in major cancer indications, including non-small cell lung cancer (NSCLC), bladder cancer and hepatocellular carcinoma (HCC). In addition, CatalYm recently announced an exploratory Phase 2 study, GDFather-NEO (NCT06059547), evaluating visugromab in combination with neoadjuvant immunotherapy in first-line muscle-invasive bladder cancer.
About Visugromab (CTL-002)
Visugromab is a monoclonal antibody that neutralizes the tumor-derived Growth Differentiation Factor-15 (GDF-15), a locally acting immunosuppressant fostering immunotherapy resistance. Neutralizing GDF-15 with visugromab reverses key cancer resistance mechanisms to reinstate an efficient anti-tumor response by reenabling immune cell activation and tumor infiltration. Visugromab has already demonstrated a good safety profile and potent and durable anti-tumor efficacy in combination with anti-PD-1 treatment in advanced cancer patients The antibody is currently being investigated in ongoing Phase 2 studies in multiple solid tumor indications.