お知らせ • Nov 08
Molecular Partners AG Presents Preclinical Proof-Of-Concept for CD3 Switch-DARPin T Cell Engager, Clinical Biomarker Analyses for MP0317 at SITC 2024
Molecular Partners AG announced the presentation of data pertaining to two programs, including preclinical proof-of-concept for a novel T cell engager Switch-DARPin in solid tumors, and comprehensive biomarker analyses from the completed Phase 1 clinical trial of MP0317. Posters will be presented at the 2024 Annual Meeting of the Society for Immunotherapy of Cancer (SITC), being held November 8-10 in Houston, TX, with the following details: CD3 Switch-DARPin: Preclinical proof-of-concept for T cell engager with enhanced function in solid tumors: The Switch-DARPin platform provides a logic-gated on/off function (the Switch) to multispecific DARPin candidates leading to immune activation only in the presence of defined antigens. This allows targeting the immune activation to tumors, increasing both efficacy and safety and opening up new opportunities for cancer treatment. T cell engagers (TCE) are a powerful class of immuno-oncology therapies but have faced a range of challenges such as high toxicity and limited specificity, particularly against solid tumors. By employing a multi-specific Switch-DARPin, Molecular Partners aims to bring additional dimensions of safety and potency to the fundamental TCE mechanism. The data to be presented at SITC provide further validation of the Company’s Switch-DARPin platform and preclinical proof-of concept that conditional T cell activation in solid tumors is feasible, as exemplified in preclinical ovarian cancer models. The presented multi-specific Switch-DARPin molecule comprises DARPins targeting: CD3, to engage and activate T cells; CD2, a co-stimulator of CD3 on T cells; Mesothelin, a notable tumor antigen overexpressed across several cancer types, including ovarian cancer, and used as anchoring target for the Switch-DARPin And the Switch-DARPin, which binds either to the tumor antigen EpCAM or to the CD3 DARPin mentioned above. In a default state, the whole molecule is in closed state (or Switched off), masking the CD3 DARPin and preventing immune activation. When tumor antigens mesothelin and EpCAM are present, the Switch-DARPin switches to bind EpCAM instead of the CD3 DARPin, thereby freeing the CD3 DARPin and allowing it to bind and activate T cells. T cell activation is further enhanced through co-stimulation by the CD2 DARPin. This CD3 Switch-DARPin molecule effectively induces potent tumor regression in vivo, with reduced cytokine release, a significant toxicity event for TCEs in the clinic, compared to an unmasked CD3 with CD2 co-stimulation. In addition, co-engagement of CD2 leads to sustained T cell activation and cytotoxic capacity. Finally, masking of CD3 prevents T cell activation in the absence of tumor antigens, hence potentially allowing for silent TCEs outside of tumors. Taken together, masking CD3 may reduce the risk of CRS and provide a better safety profile to TCEs. MP0317: Comprehensive biomarker data further support CD40 activation locally in tumor microenvironment: MP0317 is a CD40 agonist designed to activate immune cells specifically within the tumor microenvironment (TME) by anchoring to fibroblast activation protein (FAP) which is expressed in high amounts in the stroma of various solid tumors. This tumor-localized approach has the potential to deliver greater efficacy with fewer side effects compared to systemic CD40-targeting therapies. The poster presents the results of a comprehensive biomarker analyses from the completed Phase 1 multi-center, open label, dose-escalation trial of MP0317 monotherapy in patients with advanced solid tumors. The research further demonstrates the ability of MP0317 to induce a targeted, tumor-localized CD40 activation and its suitability for Q3W (every three weeks) and Q1W (weekly) dosing. The CD40 pathway is activated in a broad-spectrum of cancer types and various tumor locations. Evidence of TME remodeling in patients treated with pharmacologically active doses is exemplified by increases in dendritic cells, M1 macrophages, plasma cells, and T follicular helper cells, as well as IFN? downstream activation and an increased dendritic cell maturation gene signature score. Peripheral pharmacodynamic effects aligned with the MP0317 mode of action are also seen, including increases in CXCL10 chemoattractant, transient B-cell reduction, and activation in blood. Molecular Partners is in discussion with leading academic centers regarding potential investigator-initiated combination trials of MP0317.