Merus Biclonics fully human IgG1 large-scale screening bispecific antibody platform has given rise to multiple clinically active cancer drug candidates, and can also facilitate the discovery of optimal candidates for improved ADC performance and therapeutic index. Here we demonstrate the compatibility and favorable pharmaceutical properties of Merus Biclonics conjugated with a range of linkers and payloads to generate ADClonics, with improved binding selectivity, internalization, and cancer-cell killing activity.

Discussion of the way Regeneron is taking advantage of biparatopic antibody/receptor trafficking for efficient delivery of cytotoxic payloads. Overview of Regeneron’s Pro-DXd platform that provides remarkable tumor inhibition with a widened therapeutic window.

This presentation will describe pre-clinical data informing Regeneron’s approach to enhancing the anti-tumor efficacy of T cells, focusing on the combination of costimulatory bispecific antibodies with T cell redirecting bispecifics. In addition, recent pre-clinical data from a PD-1 targeted IL-2 immuno-cytokine will be discussed, both as a single agent and in combination with other T cell engaging agents.

While 1st generation T cell engagers comprise one or more tumor-associated antigen binding domains and a CD3 binding domain, we've also begun to explore the concept of recruiting costimulatory signals via CD28 binding. Costimulation has strong potential to build off endogenous signal 1 but also to enhance the activity of CD3s. We'll describe our efforts to build and characterize CD28 bispecific antibodies against B7H3 and other targets, together with mechanistic deconvolution.

This presentation will focus on recent progress with development of bispecific T-cell engager (BiTE) molecules in solid tumors and strategies to improve response rate and durability. Preclinical data for the DLL3-targeted BiTE molecule tarlatamab in combination with standard of care and costimulatory molecules, and translation to the clinic, will be discussed.

T cell-engaging bispecific antibodies have had tremendous success in treating hematologic tumors as single agents. Overcoming the immune suppressive environment of solid tumors will likely require combination strategies using bispecific antibodies. In this presentation, we will describe the bispecific platforms developed at Rondo Therapeutics and how we plan to use these to treat solid tumors in the clinic.

Within the past decade, therapies that activate T cells and redirect them to cancer cells have changed the landscape of treatment of hematological malignancies. Key factors for a successful T cell-engaging therapeutic include selective target expression on the tumor cells with minimal-to-no expression in other tissues and a potent molecule—e.g., a bispecific antibody—that can eliminate malignant cells to achieve long-term benefit.

Increasing antibody valency is a promising approach to improve potency and exploit biology not amenable with current antibody approaches. Here we describe a novel MULTi-specific, multi-Affinity antiBODY (Multabody) platform that exploits avidity – stronger binding power – coupled with multi-specificity to deliver potent biotherapeutics with exciting transformative potential. Built on an antibody framework, Multabodies are modular and retain antibody-like developability and pharmacokinetics, creating a truly next-generation therapeutic. Multabodies have demonstrated the potential to deliver potent biotherapeutics to tackle difficult-to-treat diseases such as cancer and infectious diseases.

Inhibitory checkpoint receptor agonists have the potential to restore immune homeostasis for patients with autoimmunity but are limited by their ability to non-discriminately bind activating FcγRs. Agonists anchored to FcγRIIb, the inhibitory Fc receptor, have the potential to provide superior agonism by avoiding inflammatory cytokine responses and limiting APC activation. Development of therapies that activate multiple inhibitory pathways to regulate both sides of the immune cell synapse will be discussed.

Cytokines are key regulators of the immune system and important targets for both immuno-oncology as well as autoimmune diseases, but therapeutic use has been limited due to on-target dose-limiting toxicities. Engineering of partial-agonist cytokines and VHH-based surrogate cytokine agonists (SCAs) allows for the development of therapeutics with improved efficacy and reduced toxicity.

Overcoming systemic toxicity is the major hurdle to developing effective cancer therapies. We developed XPAT proteins (XTENylated Protease-Activated T cell engagers) that combine the specificity of an antibody with tumor-specific unmasking to maximize the therapeutic index. Multiple clinical trials investigating XPAT proteins have been initiated.

ImmTAX are TCR-based, bispecific biologics that exploit T cell redirection as a mechanism-of-action to target-disease specific intracellular antigens. It is crucial to engineer an ImmTAX-pHLA engagement which results in a signaling-competent T cell response, rather than a mere high-affinity interaction. Here, we present a high-throughput method combining Jurkat-based mammalian display, functional screening, and deep-sequencing to identify potent TCR molecules as therapeutic candidates for ImmTAX engineering.