Dr. Pham will discuss characteristics of tumor targets that may impact the successful development of BiTE® molecules for solid tumor indications and explore potential strategies to enhance activity.

T cell-engaging bispecific antibodies have demonstrated highly potent cytotoxicity against cancer cells. This potency can engender off-tumor, ontarget toxicity problems when targeting solid tumors in humans. To address this, Maverick Therapeutics has developed a novel recombinant bispecific platform called COBRA™ (Conditional Bispecific Redirected Activation), which includes two active tumor targeting domains, a half-life extension domain and inactive T cell engaging domains, that become fully active within the tumor microenvironment in a protease dependent manner. This presentation will discuss the development of these molecules and demonstrate their efficacy against human tumor cells in vitro and in vivo.

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Numab’s MATCH platform was exploited for the generation of a monovalent trispecific 4-1BB/PD-L1/HSA MATCH3 molecule (NM21-1480) that agonizes 4-1BB on anti-cancer T cells, conditionally upon binding to and blockade of PD-L1 on tumor cells. NM21-1480 shows superior efficacy over conventional CPI therapies and avoids dose-limiting toxicities of systemic 4-1BB agonism. Further, tetra-specific MATCH4 molecules are exploited to improve on safety and efficacy of conventional bispecific strategies.

Triclonics™ Engagers are multivalent molecules with three Fab arms that bind up to three different targets and designed to have long half-life, stability and low immunogenicity. The presentation will highlight: 1) the novel features and therapeutic opportunities of the Triclonics platform, 2) the characteristics of a large, diverse CD3 Fab panel discovered using the MeMo® mouse, common light-chain transgenic technology, 3) functional screening of thousands of Triclonics Engagers in T cell assays.

Hetero-multivalent antibodies targeting agonists on T cells in conjunction with tumor-associated antigens may yield therapeutics with superior biological activities and safety profiles. Teneobio’s discovery platform utilizes VH domains of fully human heavy-chain antibodies (UniAbs) to develop bi-, tri-, or tetravalent antibodies. Data from different assay types show that multivalent UniAbs can be engineered to display superior tumor cell cytotoxicity through multiple mechanisms of action.

Bispecific antibodies are promising immunotherapeutic agents for cancer therapy. A variety of CD3 proteins from different species and with various tags can accelerate the development of anti-CD3 bsAbs.

T cell-dependent bispecifics (TDB) induce T cell-mediated killing of tumor targets by engaging both tumor antigen and CD3 on T cells resulting in formation of a synthetic immunological synapse and subsequent T-cell degranulation. T cell redirecting molecules have proven efficacious in hematological malignancies, but still emerging in solid tumors. Recruiting synthetic co-stimulatory receptor signaling (signal 2) with T cell receptor activation (signal 1) has the potential to improve TDB dependent anti-tumor activity. In the present study, we studied mechanism of action of co-stimulatory receptor bispecific in combination with TDBs utilizing an in vitro image-based T cell-dependent cellular cytotoxicity (TDCC) kinetic assay that incorporated cytokine kinetic profiling and T cell marker phenotyping. Combining co-stimulatory receptor bispecifics and TDBs improved T cell functionality and target cell killing compared to TDB alone.

To develop better therapies, primary immune cell assays are used to characterize the effects immuno-oncology candidates have on the different players of the TME.

Through a number of case studies covering exhausted T cell and macrophage assays, the design and potential applications of these in vitro experiments is discussed.

A bispecific SNIPERTM antibody that selectively eliminates intratumoral regulatory T-cells (Treg) while not inducing systemic Treg depletion will be described. As the Treg targeted SNIPER™ did not change the levels of Tregs in the periphery, this SNIPER™ may be an effective way to relieve the immunosuppressive microenvironment in tumors leading to stronger anti-tumor efficacy while decreasing the systemic autoimmune toxicities associated with other therapies.

ATOR-4224 is a tumor-directed CD40 x EpCAM bispecific antibody designed to improve cross-presentation of tumor neoantigens and boost the priming of neoantigen specific T-cells. We demonstrate that mode of action is dependent on high expression of EpCAM on tumor derived extracellular vesicles and tumor cells, and that dual targeting of CD40 and EpCAM mediates a superior anti-tumor effect and decreased unwanted systemic immune activation compared to monoclonal CD40 antibody control.