Mesothelin (MSLN) is a promising target for cancer therapy, but the shedding of MSLN limits therapeutic efficacy by sequestering antibody-based therapeutics. We developed a bispecific T cell engager and CAR T cells that target a membrane-proximal, non-shed epitope of MSLN. A single intravenous dose induced complete regression of MSLN-expressing tumors in immunocompetent mice, accompanied by robust T cell expansion, durable antitumor immunity, and enhanced immune activation within the tumor microenvironment. These findings demonstrate that targeting a non-shed epitope of a tumor antigen can overcome a key barrier to antibody-based cancer immunotherapy.

T cell engagers (TCEs) can redirect T cells to target and destroy solid tumors, but their therapeutic window is constrained by the number of antigens that are truly tumor-specific and remain stable under immune pressure. Neoantigens derived from oncogenic driver mutations are both unique to tumor cells and essential for their survival. Clasp’s TCEs exhibit exceptional specificity and strong anti-tumor efficacy in preclinical studies, representing a highly precise immunotherapy strategy.

Acute myeloid leukemia (AML) is an aggressive cancer driven by uncontrolled proliferation of immature myeloid blasts that express high CD123 levels, a target limited by off-tumor toxicity in CD3×CD123 T cell engagers. We developed NTB-921, a pan-d x CD123 bispecific that harnesses innate-like ?d T cell cytotoxicity against CD123+ AML cells to overcome this toxicity. NTB-921 induced ?d T cell-mediated cytotoxicity across varying CD123 expression levels, promoted T cell proliferation, and enhanced innate sensing. Despite activity comparable to CD3×CD123 engagers, NTB-921 elicited markedly reduced cytokine release and no cytotoxicity against healthy CD123+ monocytes, supporting clinical development for R/R AML.

T cell engagers (TCEs) have demonstrated significant efficacy. However, their use in solid tumor therapies has been hindered by off-target toxicities arising from the expression of tumor-associated antigens (TAAs) on healthy tissues. To overcome this limitation, we introduce here an innovative dual-targeting trispecific T cell engager. This modality integrates an anchoring arm to target TAA1 and an affinity-attenuated active arm for TAA2, enabling precise discrimination between tumor and normal tissues. By doing so, it substantially improves the therapeutic index (TI). The enhanced TI of these TCEs is achieved through meticulous engineering, incorporating optimizations in target affinity, overall avidity, and molecular geometry.

We present a plug-and-play platform for generating next-generation T cell engagers using disulfide-linked Fc–Fc?R fusions. Covalent assembly enables stable, multispecific complexes combining bivalent tumor targeting with T cell–directing or immunomodulatory modules. Compatible with standard expression, this system supports rapid generation of engagers with tunable avidity and strong antigen-dependent cytotoxicity, providing a modular framework to improve selectivity and reduce off-target activity.

KT209 is a trispecific antibody (CD19×CD20×CD3) designed to redirect endogenous T cells for potent B-cell killing with reduced cytokine release. In vitro, it demonstrated superior cytotoxicity against CD19-low or CD20-low leukemia cells compared with Blinatumomab and Glofitamab while maintaining lower cytokine production. In cynomolgus monkeys, KT209 induced durable B-cell depletion with only transient cytokine elevations and no persistent lymphocyte exhaustion, supporting a favorable therapeutic index.

The PrimeBody platform uses protease-cleavable linkers and affinity-tuned masking to create tumor-activated biologics with improved safety and efficacy. VOR-101, a masked Fc-enhanced CD47 blocker, remains inert systemically but activates in tumors, achieving high selectivity, increased exposure, durable regressions, and an improved therapeutic index. Applications to cytokines and T cell engagers will also be discussed.

Emerging clinical validation of costimulatory therapeutic approaches highlights their potential to enhance the depth and durability of anti-tumor responses in cancer patients. Here, we describe co-stimulatory design strategies that combine two tumor antigens to maximize tumor engagement. This new EVOLVE platform combines integrated CD2 co-stimulation with multi-antigen tumor targeting to drive selective tumor-directed CD2 co-stimulation and overcome single-antigen dependence, with the potential for enhanced and broader anti-tumor efficacy in patients.

IL-7 is a promising cytokine that could enhance anti-tumor response by improving the fitness and persistence of T cells in the tumor environment. Despite being well tolerated, clinical use of IL-7 in cancer has been limited by systemic expansion of T cells. To target IL-7 in the tumor microenvironment and limit systemic activation, we engineered a potency reduced IL-7 cytokine into a multispecific antibody with anti-tumor activity.