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This Week’s News?
Trends – Trispecific Antibodies
Trispecific antibodies are an advanced class of engineered therapeutic proteins designed to simultaneously bind three distinct targets, offering enhanced precision and versatility in treating complex diseases, particularly cancer and immune-related disorders. By combining three binding sites within a single molecule, they can bridge immune cells to tumor cells, block multiple disease pathways, or engage multiple antigens for improved efficacy. This innovative approach expands the potential of antibody-based therapies, addressing limitations of traditional monoclonal and bispecific antibodies while paving the way for more targeted and effective treatments.
Last week, AbbVie penned a $1.05B deal for 先声再明 ’s novel trispecific T-cell engager antibody, SIM0500, which is currently in Phase 1 clinical trials in patients with relapsed or refractory multiple myeloma (MM), in both China and the U.S. SIM0500 is a humanized trispecific antibody that targets GPRC5D, BCMA, and CD3. The molecule features a low affinity/high target-activating CD3 engaging arm and binding sites for the two tumor antigens: G-Protein-coupled receptor class 5 member D (GPRC5D) and B-cell maturation antigen (BCMA). It has shown strong T cell cytotoxicity against multiple myeloma (MM) cells by leveraging a combination of various antitumor effects.?
基石药业 also announced the recent submission of clinical trial application in Australia for CS2009, a trispecific targeting PD-1, VEGFA, and CTLA-4 simultaneously, maintaining balanced affinity for PD-1 and CTLA-4. This design enables preferential targeting of double-positive tumor-infiltrating T lymphocytes (TILs), effectively blocking both PD-1 and CTLA-4 while sparing CTLA-4 on single-positive cells. This approach could potentially reduce systemic toxicity without compromising efficacy. Additionally, CS2009 induces high and rapid internalization, leading to the down-regulation of PD-1 and CTLA-4 expression on the TIL cell membrane.?
Building on the success of T-cell-engaging bispecific antibodies (BiTEs) that link tumor cells and T cells for effective immune-mediated tumor killing, a novel approach to advance this concept involves using Fcγ receptor 1 (FcγR1)-coated nanoparticles (FcγR1-CMNPs) as a delivery platform to immobilize multiple monoclonal antibodies (mAbs) through receptor–ligand interactions. By attaching αCD3 and αCD20 to these nanoparticles, a bispecific nanoantibody (CMNP@CD3 × CD20) was created, demonstrating enhanced T-cell and tumor cell interaction and potent anti-tumor effects in vitro and in vivo. This innovative system provides a simplified, flexible method for developing trispecific or multispecific antibody-based therapies, offering new possibilities for precision cancer treatment.
Another trispecific antibody, TAVO412,?targeting EGFR, c-Met, and VEGF-A, is under clinical development for treating solid tumors with mechanisms that inhibit tumor growth by blocking key signaling pathways, enhancing Fc effector functions, overcoming drug resistance, and inhibiting angiogenesis. Preclinical studies in 23 CDX and 9 PDX tumor models demonstrated strong anti-tumor activity. Using next-generation sequencing, transcriptomic biomarkers were identified based on gene expression profiles correlating with treatment response. A 21-gene biomarker set and a Linear Prediction Score (LPS) model were developed to predict treatment efficacy with 78% accuracy in CDX models, validated in PDX models. These findings support precision medicine approaches to optimize patient selection for TAVO412 therapy.
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