• How do we go about selecting the right tumors for the right MOA?
  
• How can we explore novel approaches to MOA-driven patient enrichment?
• How can we develop options for rational combinations?​

Development of bispecific T Cell Engagers (TCEs) against solid tumors has been fraught with unique challenges, including immune suppressive tumor microenvironment, tumor heterogeneity, variable levels of target expression on tumor cells as well as healthy tissue, and off-target, peripheral T cell activation. In my presentation, I will discuss learnings from recent advances and ongoing innovation in this field and share my thoughts on factors one needs to consider when developing novel TCEs, including design characteristics of the molecule, target selection, adverse event management, biomarkers, dose selection/optimization, and companion/complementary diagnostics.

Rondo has developed CD28 agonistic antibodies for bispecific engineering to treat solid tumors. While T cell engagers have proven success in hematologic cancers, efficacy in solid tumors remains limited. Co-stimulatory bispecifics have the potential to enhance T cell responses in immunologically hot tumors. RNDO-564, a CD28 x Nectin-4 bispecific antibody has an affinity-tuned CD28 binder, potent anti-tumor activity, and favorable developability features, making it an ideal therapeutic candidate for mUC.

The presentation will highlight IGI's BEAT technology and its role in engineering bispecific and trispecific immune cell engagers to overcome tumor immune escape. It will cover the preclinical development of two molecules: a bispecific CD47-CD38 innate cell engager and a trispecific BCMA-CD38 T cell engager, both in Phase I clinical trials and recently published in Nature Communications and Nature Cancer (2024).

T cell engagers (TCEs) in solid tumor therapies has been hindered by off-target toxicities arising from the expression of 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 and substantially improves the therapeutic index (TI). Collectively, this work provides a robust, generalizable framework for designing immune engagers with improved safety and efficacy, opening the door to broader therapeutic applications.

Recent clinical results show the ability to target intracellular proteins through peptides presented by human leukocyte antigen (pHLA), opening up a unique avenue to targets inaccessible to conventional biologics. Bispecific T cell engagers are an effective therapeutic modality to redirect T cell immune responses towards tumors. However, there is still significant unmet need in a number of solid tumor indications with limited treatment options and few pHLA targets. Using a high-throughput discovery platform utilizing experimental screening and machine learning approaches to map patient T cell immune responses to their respective pHLA targets, a novel wildtype tumor-associated pHLA target with sufficient tumor versus normal expression has been identified. This target contributes directly to tumor stability and growth, and is widely expressed in colorectal cancer, triple-negative breast cancer, and squamous non-small cell lung cancer among other indications. 3T-403, a CD3 bispecific T cell engager utilizing a T cell receptor mimic (TCRm) antibody has been developed to this novel target. The pHLA binding arm of 3T-403 has undergone specificity analysis using classical alanine scan as well as analysis via a novel high-throughput combinatorial library to de-risk potential pHLA off-targets. Potency assays conducted with 3T-403 show lysis against a panel of tumor cell lines, while minimal cytotoxicity was observed on primary healthy tissues, which provides a therapeutic window. Investigational new drug (IND) application completion is expected early 2026. Such a bispecific T cell engager against a novel target shows significant promise to address multiple solid tumor indications.

The development of 3D tumor models marks a significant advancement in cancer research, providing more accurate representation of tumor biology and drug response than traditional 2D cultures. Our research utilizes high-content imaging to explore effects of hypoxia on tumor progression and treatment resistance within complex 3D models, including spheroids and organoids. This approach not only deepens our understanding of tumor biology but also opens new avenues for novel hypoxia-targeted therapies.

Antigen escape and suppressive signals limit NK cell immunotherapy. We previously described the TriKE platform, which drives NK cell antigen-specific activation while also providing an IL-15 signal. To enhance the TriKE capabilities, we built backpacks (PACCs), that attach to the IL-15 moiety in the TriKE to add one more antibody fragment in the complex. Using TriKE-PACC molecules, we can mediate dual antigen targeting against B7H3 and a second tumor antigen (either CD133 or PSMA) in several cancer settings. TriKE-PACC molecules targeting B7H3 and blocking ADAM17 mediated CD16 shedding can increase NK cell anti-tumor activity in the tumor microenvironment.

The hERG1 potassium channel and β1 integrin form a complex that localizes in Lipid Rafts in Pancreatic Ductal Adenocarcinoma (PDAC) cells. A single-chain bispecific antibody (scDb-hERG1-β1) targeting this complex potentiates MbetaCD and statin effects on intracellular signaling. Different statins, in synergy with scDb-hERG1-β1, produce anti-neoplastic effects, enhancing chemotherapeutic sensitivity in vitro and in vivo.

This presentation will discuss high-throughput proteomics for discovering multi-epitope nanobodies. These nanobodies enable the design of multispecific antibodies, enhancing therapeutic potential. The method facilitates rapid identification and characterization of diverse binding domains for complex targeting strategies.