Human model systems are highly important in instructing the selection of antibody design for efficacy parameters and providing safety information. I will provide drug candidate examples of how the ID.Flow system, a system based on fresh human whole blood in circulation, can enable analyses of cellular biodistribution, target and off-target engagement, effector cell analyses, cytokine release risks, antibody uptake, and evaluation of interactions with complement and coagulation proteins. Examples will include data from multispecific antibody drug candidates along with peptide conjugates.

The use of cytokines for immunotherapy shows clinical efficacy but is frequently accompanied by severe adverse events caused by excessive and systemic immune activation. These challenges were addressed by engineering a fusion protein of a single, potency-reduced, IL15 mutein to a PD1-specific antibody. This cis-delivered cytokine allows for cell specific targeting and lead to CD8 T cell-dependent antitumor efficacy without exacerbating body weight loss in syngeneic tumor models.

Bispecific T cell engagers (TCE) were recently approved for relapsed/refractory multiple myelomas. Yet, primary resistance occurs in one third of patients, and most responders eventually develop acquired resistance. Through a multi-omics single-cell characterization of resistant cases, we uncovered various mechanisms of resistance to TCE. Molecular analysis of target antigens will be key to select the most appropriate TCE for each patient, and to design combination and sequencing immunotherapy strategies.

The optimised design and differentiated mechanism of action, enhanced antitumour activity, and safety of TriTCE Co-Stim antibodies compared to conventional bispecific T cell engagers will be presented.

ImmTAC molecules are bispecific T cell engagers utilising engineered T cell receptors (TCRs) to target and kill tumour cells. Here, we present the development of IMC-R117C, an ImmTAC targeting a peptide from PIWIL1, a novel colorectal cancer target, presented on HLA-A2. Once the optimal weak affinity TCR was identified, its specificity profile was determined and engineering approaches were applied to improve molecule affinity whilst minimising off-target binding, ensuring high ImmTAC efficacy and specificity.

The Epidermal Growth Factor Receptor (EGFR) is frequently found to be mutated in non-small cell lung cancer (NSCLC). Oncogenic EGFR has been successfully targeted by tyrosine kinase inhibitors, but acquired drug resistance eventually overcomes the efficacy of these treatments. Unfortunately, there is a great need to treat patients with this inherent resistance to immuno-oncology (IO) monotherapy.  The combination of amivantamab (fully human bispecific antibody that binds to the EGFR and MET receptor) binding EGFR and EGFR TKIs, can simultaneously target both the extracellular and intracellular catalytic domains of EGFR resulting in potent anti-tumor responses in mutant NSCLCs.  We demonstrate how TAVO412, a trispecific cMET x EGFR x VEGF in combinations with standard of care treatments have more potent anti-tumor responses in a variety of solid tumors.

Recent multispecific antibodies and CAR T are being designed to target multiple antigens simultaneously, and offer a promising approach to overcome tumour escape mechanisms and enhance anti-tumour efficacy. These molecules can bridge tumour cells and immune effector cells, thereby promoting a robust and targeted immune response. Moreover, multispecific antibodies may have a role improving tumour penetration and mitigating on-target, off-tumour toxicity.

Antibody-drug conjugates (ADCs) have shown remarkable clinical efficacy, resulting in improved outcomes for several tumour types. Resistance to ADCs can arise through various mechanisms, including antigen downregulation, drug efflux pumps, alterations in drug payload metabolism, and changes in intracellular trafficking pathways, necessitating the development of strategies to counteract these resistance pathways. Synergistic effects are observed when ADCs are combined with novel agents such as immune checkpoint inhibitors, tyrosine kinase inhibitors, and other targeted therapies, enhancing anti-tumour activity and potentially overcoming resistance mechanisms. Innovative approaches to overcoming resistance include optimising linker stability, developing next-generation ADCs with novel payloads, and using combination therapies.

Antibody-drug conjugates (ADCs) represent a rapidly evolving therapeutic modality in oncology, leveraging the specificity of monoclonal antibodies to deliver cytotoxic agents directly to tumour cells. By targeting tumour-specific antigens, ADCs aim to maximise efficacy while minimising off-target toxicity. Recent advancements in ADC technology, including novel linker chemistries and potent cytotoxic payloads, have improved therapeutic indices and broadened their applicability to various malignancies. ADCs have demonstrated substantial efficacy in hematologic cancers and solid tumours, with ongoing research exploring their use in combination therapies and overcoming resistance mechanisms.