Main Conference Day 2Wednesday, 11 June 2025 - BST (British Summer Time, GMT+1)

Targeting tumors with γ9δ2T cells resulted in poor clinical outcomes, mainly due to the low affinity of γ9δ2TCRs for tumor antigens. We have developed affinity-enhanced γ9δ2TCRs, which led significantly improved tumor control in both in vitro and in vivo preclinical models, paving the way for next-generation γ9δ2TCR-based immunotherapies.

IgE antibodies exert pathogenic effects in allergies and protective anti-parasite immunity via high-affinity Fcε receptors on tissue-resident effector cells. We generated IgEs recognising cancer-associated antigens and translated the first-in-class agent to clinical testing. IgEs trigger pro-inflammatory effector recruitment and induction of hyperinflammatory macrophages to inhibit immunosuppression in the tumour microenvironment.

ALL has become a model disease for novel immunotherapeutic approaches Here, we report on our studies using antibodies of either IgG1 or IgA2 isotype to mediate killing of ALL cells in vitro and in PDX models. These results suggest to investigate the clinical efficacy of IgA antibodies in combination with myeloid checkpoint blockade in ALL.

IgG-based therapeutics may eliminate a target via Fc-mediated effector mechanisms. However, there is a need for more potent formats. The TandemAb concept combines structural elements of IgA with that of IgG, and results in tailored designs with favorable plasma half-life and engagement of effector molecules that can eradicate tumor cells and bacteria.

Antibody Fragment Drug Conjugates (FDCs), a new product class tailored for solid tumours promise many advantages over ADCs including rapid tumour penetration and faster systemic clearance. However, these have been technologically-challenging to apply in oncology. Our novel approach enables high-Drug:Antibody Ratios (DARs) whilst retaining effective binding and other favourable biophysical properties. To achieve this, single-chain Fvs and other recombinant antibody formats must be considered in context with complex linker-payload chemical moieties. This platform technology has led to our lead product, ANT-045 is a cMET-targeted FDC addressing a wide range of solid tumours. ANT-045 demonstrates superior tumour cure efficacy in cMET high, moderate and low CDX and PDX gastric cancer xenograft models and better tolerability compared to the leading competitor ADCs. In a non-GLP, non-human primate study, ANT-045 was well tolerated demonstrating no signs of the usual dose-limiting adverse effects seen with ADCs (neutropenia, thrombocytopenia) with a predicted half-life in humans of around 12-14 hours supporting a viable clinical dosing strategy with a wide therapeutic window. Insights into how FDCs behave in vivo through quantitative and qualitative imaging/uptake studies and toxicological parameters will be shared and how these have informed our follow-up products.

To address the limited therapeutic window of several targeted cancer therapies we developed a chemical cleavage reaction (Click-to-Release) that allows in vivo control over drug activity. It enables controlled on-target cleavage of ADCs in the TME through a click reaction with a trigger molecule given in a second step, expanding the target scope to non-internalizing receptors. And it enables off-target deactivation of radioimmunotherapy, by selective radiolabel cleavage and clearance from circulating radioimmunotherapeutics, decreasing bone marrow toxicity. This contribution will cover examples from both ends of the therapeutic window.

The key components of Synaffix’s proprietary ADC technology GlycoConnect®, HydraSpace®, and  the toxSYN® platform enabling ADCs with best-in-class therapeutic index potential will be presented. Next, an overview on the pipeline of more than 16 GlycoConnect® ADCs that are rapidly being advanced by our partners will be provided, followed by sharing clinical development insights on the most advanced assets.

Immune-stimulating antibody conjugates (ISACs) utilize an innate immune agonist to promote lymphocyte activation in the tumor microenvironment, ultimately resulting in tumor regression and immune memory. While this technology has elicited powerful efficacy in various preclinical models, there have been a number of clinical setbacks and disappointments that have tempered the enthusiasm for this technology. We will describe the current state of the field of ISAC technology and will describe new ISAC designs that are being employed by our lab to overcome some of the reported clinical challenges. Specifically, we will focus on the role of Fc-gamma receptors in the efficacy and toxicity of ISACs.