We have designed a costimulatory multispecific platform with conditional cis CD28 co-stimulation to widen the therapeutic window through optimized T cell engagement and enhanced T cell functionality. The design and application of this platform across diverse tumor-targeting strategies, including logic-gated, 2+1+1, and peptide–MHC (pMHC)-targeting approaches, will be discussed. We will highlight the benefits of integrated co-stimulation, including enhanced and sustained T cell functionality and antitumor activity compared with conventional bispecific T cell engagers.

While T cell engagers have had compelling success in the treatment of hematologic malignancies, their development for the treatment of solid tumors has been more challenging. Nevertheless, newer-generation approaches utilizing Xencor’s XmAb 2+1 formats—coupled with affinity/avidity tuning for improved tumor/normal selectivity—have shown strong clinical progress. Coupling these approaches with costimulatory bispecifics targeting CD28 or CD2 offers a new avenue for further activity and/or selectivity enhancement.

Co-localizing “signal 1” (TCR/CD3) and “signal 2” (costimulation) at the tumor cell surface by combining CD3-engaging and costimulatory bispecific antibodies can drive deeper and more durable antitumor responses. This presentation will describe Regeneron’s costimulatory bispecific platform and preclinical data on two multiple myeloma-targeted molecules that enhance T cell activation, cytokine production, and tumor killing in combination with a BCMAxCD3 T cell engager.

Co-stimulatory multispecific antibodies offer the opportunity to integrate target-cell recognition, T-cell engagement, and immune activation within a single molecule, but their activity depends on coordinated tuning of each component rather than simply adding specificities. Drawing on our experience developing multispecific T-cell engagers and immune-enhancing molecules, this presentation will discuss how target selection, affinity, valency, geometry, and molecular configuration add to the design complexity and how to navigate them.

Despite the transformative impact of Immune Checkpoint blockade, many cancers remain unresponsive to anti-PD-1/PD-L1 therapies. Platinum Resistant Ovarian Cancer (PROC) is one such immunologically ‘cold tumor’ and remains an area of high unmet medical need. We have developed a bispecific antibody approach to safely target the innate immune checkpoint receptor CD47 selectively on tumor cells. Combining tumor-selective CD47 blockade with PD-1 inhibition engages complementary innate and adaptive immune mechanisms, unlocking anti-tumor immunity leading to durable responses in heavily pretreated PROC patients.

MAIT engagers, a type of T cell engager, direct MAIT cells to efficiently kill cancer cells. However, unlike CD3 engagers that activate all T cells, MAIT engagers are specific to the abundant MAIT cell population and do not induce cytokine release syndrome or activate the regulator T cell population in solid tumors. These differences create an effective therapeutic window and should lead to better responses in the clinic.

ASP6958 (VIR-5500) is a PSMA-targeted, protease-activated dual-masked T-cell engager under early phase clinical development for prostate cancer.Emerging clinical data from the dose escalation of the VIR-5500-V101 Phase 1 Study, show preliminary evidence of tolerability and anti-tumor activity in heavily pre-treated patients with metastatic castration resistant prostate cancer.

Xilio Therapeutics is leveraging its clinically validated masking technology to develop tumor-selective I-O therapies designed to unlock the potential for durable efficacy by focusing anti-tumor activity within the tumor microenvironment and limiting severe side effects associated with systemically active I-O agents. We will be presenting data on XTX501, our clinical-stage bispecific PD-1/masked IL-2 antibody fusion protein and our masked T cell engager programs targeting CLDN18.2 and PSMA+STEAP1 currently in preclinical development.

By targeting the two critical receptors of a signaling complex on orbital cells, OLN102 will provide improved efficacy, safety, and convenience for patients.  Stimulatory autoantibodies targeting Thyroid Stimulating Hormone Receptor (TSHR), complexed on orbital cells with the IGF-1 receptor, drive inflammation adipogensis and fibrosis. Simultaneous targeting of both signaling receptors has the potential to provide acute and sustained improvement in orbital symptoms by simultaneously disrupting the autoimmune process in the thyroid. The biological rationale and pharmacologic benefits of targeting both receptors in this pathologic complex will be presented.

The development of multispecific therapeutics for solid tumors requires experimental systems that capture the complexity of the tumor microenvironment. This presentation will showcase high-throughput 3D tumor models that integrate measurements of tumor penetration, functional activity, and hypoxia biology to evaluate ADCs, T-cell engagers, immunotherapies, and combination approaches. Emerging data demonstrate how 3D models can reveal critical differences in therapeutic performance that are often missed in conventional 2D assays.