BPT567 is a PD1-IL18 immunocytokine harboring an engineered, optimized IL-18 payload. In cells expressing PD-1, BPT567 exhibits significantly enhanced potency due to cis-signaling. BPT567 induces the tumor-selective activation and expansion of CD8+ T effector memory (Tem) cells and concomitant strong local IFNg release. CD8+ Tem cell expansion translates into potent antitumor efficacy in multiple syngeneic mouse tumor models including models resistant to PD-1 inhibition.

Oncolytic viral vaccines are an emerging class of immunotherapeutics. As versatile engineering platforms, they can be harnessed for tumor-targeted delivery of bispecifics, checkpoint modulators, and cytokines. This talk will highlight recent preclinical developments and translational research in this field.

The HapImmune technology exploits small-molecule covalent inhibitors to create distinct neoantigens that selectively mark cells harboring an intracellular disease driver. We have developed antibodies that bind to FDA-approved KRAS(G12C) inhibitors conjugated to KRAS(G12C) peptides presented by HLAs, but not to the free inhibitors. Bispecific T cell engagers selectively kill inhibitor-resistant cancer cells upon inhibitor treatment. Our technology unites targeted and immune therapies, thereby expanding therapeutic opportunities against intracellular proteins.

Biologics have revolutionized the cancer treatment and impressive therapeutic effects of bispecific antibodies (BsAb) and Ig-fusion concepts resulted in approval in oncology and beyond. We saw great achievements in technical/clinical development of IgG-like BsAbs such as the Crossmab format (e.g., Faricimab approved in ophthalmology) and smaller bispecific Dutafabs line up allowing combined inhibition of different pathological pathways in the eye and there is more progress and clinical evaluation of engineered large molecules (classical or engineered antibodies) in infectious diseases and neuroscience. We would like to show recent developments for BsAbs - from incremental improvements to Brainshuttle.

The talk will present a comprehensive comparison of formats for the generation of robust bispecific antibodies through fusion of single-domain antibodies on IgG scaffolds and a toolbox of complementary methods for in-depth analysis of key features, such as in-solution dual antigen binding, thermal stability, and aggregation propensity, to ensure high bsAb quality. Furthermore, it will present novel in silico designed humanized single-domain antibody phage display libraries with maximal functional diversity for generating fusion partners.

The eIg platform technology was used to generate a set of bispecific TCEs targeting EGFR and CD3. In total, 11 different TCE formats were analyzed for binding to target and T cells, T cell-mediated killing of tumor cells, and for the activation of T cells. Our findings support that screening of a panel of formats is beneficial to identify the most potent bispecific TCE, and that format matters.

TCER are next-generation T cell receptor (TCR)-based T cell-engaging bispecifics targeting peptides presented by HLA-molecules on tumor cells. The use of a high-affinity TCR domain and a low-affinity T cell recruiter coupled to an Fc part for half-life extension has been shown in preclinical experiments to optimize efficacy, safety, and dosing schedule. Immatics is developing a broad pipeline of TCER addressing different indications and large patient populations.

ImmTAC is a soluble TCR-antiCD3 bispecific that can redirect T cells to target cancer cells. A high affinity TCR arm enables the possibility to target a broad range of intracellular cancer antigens presented by cell surface MHC molecules. By enhancing the affinity of TCR over a million-fold, there is a possibility to target poorly presented cancer-specific antigens that are otherwise undetectable to the immune system. A suite of tools is utilised to monitor the specificity of the high-affinity TCRs. We will present data to demonstrate that affinity and specificity can be engineered to turn TCRs into potential therapeutic bispecifics.

gdT cell inspired therapies gained substantial moment during the last decade resulting in multiple strategies for how to harness the anti-tumor potential of gdT cells for therapeutic concepts. I will discuss state-of-the-art in the context of current clinical data from most recent concepts as well as the potential future formats.

Bispecific antibodies engaging NKG2D or NKp30 and binding a tumor-associated antigen were generated to sensitize tumor cells to NK cell-mediated killing. The impact of molecular architecture on cytotoxic activity and the capacity to act as co-stimulators for FcgRIIIa-triggered anti-tumor responses will be discussed. This approach may represent a promising strategy to modulate stronger NK cell-mediated antitumor responses and to boost the activity of therapeutic antibodies.