Targeted protein degraders offer a highly specific therapeutic approach to modulate disease-relevant proteins while potentially minimizing systemic toxicities associated with global inhibition. By selectively eliminating pathogenic proteins, degraders address challenges posed by targets with multiple roles across tissues. We will discuss the principles behind DuetMab Degraders, which are designed to harness selective protein degradation to achieve precise therapeutic effects while aiming to mitigate toxicity.

Deka Biosciences developed a novel multispecific platform delivering potent cytokines directly to the tumor microenvironment (TME), leveraging IL-10 to mitigate systemic toxicity. Our lead, DK210 (EGFR), a multispecific IL-2/IL-10 fusion with EGFR-targeting, shows promising clinical safety. Dosed in 39 patients, it achieved high TME exposures without vascular leak or cytokine release syndrome, validating this multispecific cytokine engineering for safer, more effective immunotherapies.

NovalGen’s AutoRegulation (AR) technology provides precision control of immunotherapies that safeguards against both overactivation and exhaustion of the immune system, improving therapeutic index, promoting community-based treatment, and enhancing clinical efficacy. AR is an intrinsic element of NVG-222, a ROR1-targeting T cell engager (TCE) for oncology, and NVG-666, a CD19-targeting TCE for autoimmune disease, both of which are clinic-ready with first-patient dosing expected within the next year.

Although anti-PD-(L)1 therapies have been transformative, many patients dont respond. We developed IDP-002, a PD1xCD6 bsAb that facilitates PD-1 blockade driven by cis-binding to CD6, enhanced PD-1 receptor occupancy and synapse sequestration. IDP-002 promotes effector T cell proliferation and cytotoxic responses and has reduced effects on Tregs over effector T cells. IDP-002 activity derives from combination of complete PD-1 blockade and the engagement of unique signaling pathways downstream of CD6.

This presentation will explore the unique mechanisms of action of Amivantamab (EGFR NSCLC) and Tebentafusp (uveal melanoma), two bispecific antibodies approved for solid tumors. It will trace their paths to FDA approval, from preclinical development through first-in-human and pivotal clinical trials, and examine the distinct safety profiles of each agent to provide insights into their therapeutic potential and clinical integration.

This presentation addresses strategies to improve clinical outcomes for immune checkpoint inhibitors and bispecific drugs. We'll discuss preclinical validation and modeling techniques used to predict efficacy and derive the mechanism of action. The goal is to identify and mitigate factors that contribute to clinical failures, enhancing the development of these therapies.

The field of immune engagers for solid tumors is rapidly advancing. As more products reach early-phase clinical trials, new safety signals are emerging along with novel management strategies. Natural killer cells in particular offer a potential for safer administration of immune engagers.  In this session, we will review the safety data collected from our CD33-targeting tri-specific killer engager molecules and how this is being translated to our solid tumor platform.

On-target off-tumor toxicity is a key issue that can limit the clinical success of T cell engager molecules in solid tumors. Using examples from both the preclinical and clinical settings, this presentation will review several engineering strategies that have been employed to increase the therapeutic index of T cell engager molecules to spare normal tissues toxicity.

Conditional activation of target pathways with bispecific antibodies can allow (re)-invigoration of the immune response at the preferred site of action within the tumor microenvironment (TME). Acasunlimab (DuoBody-PD-L1x4-1BB) and GEN1042/BNT312 (DuoBody-CD40x4-1BB) are two novel investigational bispecific antibodies designed to reshape key TME elements with targeted T-cell activation. Here we show how mathematical models of NSCLC and HNSCC, together with preclinical findings, are used to optimize bispecific design and dosing strategy.

This presentation addresses protecting innovations in multispecific antibody development. We'll discuss key intellectual property strategies, including patent and trade secret considerations. The aim is to provide an overview of securing novel antibody technologies in a competitive landscape.