Acute myeloid leukemia (AML) is an aggressive cancer driven by uncontrolled proliferation of immature myeloid blasts. AML blasts express high CD123 levels, a target limited by off-tumor toxicity. Gamma delta (δ) T cells offer innate-like and adaptive cytotoxicity against CD123+ AML cells. We have developed NTB-921, a pan-d x CD123 bispecific that potently and selectively engages δ T cells to kill CD123+ AML cells, supporting clinical development for R/R AML.

Mucosal-Associated Invariant T cells (MAITs) are an abundant subset of non-conventional cytotoxic CD8 T cells resident in most tissues and solid tumors. MAIT engagers induce potent MAIT-mediated cytotoxicity of cancer cells. At difference to CD3 TCEs, MAIT engagers do not induce CRS nor activate regulatory T cells in the tumor microenvironment, permitting optimal dosing and improved anti-tumor activity. Increased safety and activity of MAIT engagers affords a large therapeutic window.

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.

Bispecific T cell engager (TCE) therapies have demonstrated transformative clinical success in the treatment of hematological cancers, but the success of TCEs in the solid tumor space has been hindered by the lack of antigens that are sufficiently selective for malignant cells. Here, we identify Preferentially Expressed Antigen in Melanoma (PRAME), an intracellular cancer testis antigen (CTA), as a highly tumor selective antigen. Using mass spectrometry, we identified a peptide, PRAME425, as the most abundant PRAME peptide presented by major histocompatibility complex I (MHCI) in cancer cell lines. We describe the discovery of antibodies that bind specifically to PRAME425 pMHC with TCR-like binding geometry and do not recognize MHC alone or off-target pMHCs. By formatting these novel antibodies into a highly potent TCE format, we demonstrate PRAME425 pMHC-specific killing of tumor cells, representing a new class of anti-PRAME pMHC biologics.

We present a plug-and-play platform for generating next-generation T cell engagers using disulfide-linked Fc–FcγR 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.

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.

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.

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.

While standard in vitro reporter assays favor membrane-distal costimulatory fusion proteins due to simple target crosslinking, in vivo efficacy requires a tight, coordinated immunological synapse. When combined with a CEA-TCB bispecific antibody, the CEA membrane-proximal variant T84.66-LCHA-4-1BBL—the weakest in vitro candidate—demonstrated superior in vivo anti-tumor efficacy and CD8+ T cell infiltration. Therefore, early candidate screening must incorporate intended T cell engager partners to ensure synaptic compatibility.

Targeting of costimulatory receptors holds the promise to promote sustained T cell activity and tumor cell killing in solid tumors. We will highlight our costimulatory receptor selection, CD28 platform design and the development of our bispecific antibodies with an optimized therapeutic window. An update of the clinical development of our precisely tuned CD28 x Nectin-4 bispecific antibody, RNDO-564, will be provided.

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.