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

ImCheck has created a set of bispecific antibodies, exploring different formats and valency to modulate anti-BTN3A agonist potency. Building on these modalities allowed to explore Vγ9Vδ2 T cell stimulation via BTN3A-mediated signal 1, immune checkpoint blocking and cis/trans anchoring to potentiate anti-tumor activity.

HVEM, a member of the TNF receptor superfamily (TNFRSF14), interacts with several molecules, including BTLA, CD160, and LIGHT. HVEM is expressed not only on hematopoietic cells but also on non-hematopoietic cells, which allows it to regulate both the priming phase of T cells in the draining lymph node and the effector phase of the T cell response at the inflamed tissue site. The engagement of HVEM with BTLA provides negative signals, while LIGHT engagement delivers bidirectional positive costimulatory signals, promoting T cell survival and effector functions.

T-cell engaging bispecific antibodies have had tremendous success in treating hematologic tumors but have shown limited efficacy in solid tumors. Alternative strategies for engaging the immune system employing safe and tunable bispecific antibodies are needed to overcome the challenges of solid tumors. In this presentation, we describe the bispecific platforms developed at Rondo Therapeutics and highlight progress on our lead program, RNDO-564, a CD28 x Nectin-4 bispecific antibody for treatment of metastatic bladder cancer.

To better harness the anti-tumor activity of T cells on top of immune checkpoint inhibition, we generated a PD-L1/CD28 bispecific antibody using our κλ-body platform to promote antitumor function through a dual mechanism of action, immune checkpoint inhibition and T cell co-stimulation. In this presentation, we provide in vitro and in vivo evidence to confirm the safety and efficient anti-tumor activity of this dual-targeting strategy.

Costimulation of tumor-infiltrating T lymphocytes by anti-4-1BB monoclonal antibodies has shown anti-tumor activity in human trials but can be associated with significant off-tumor toxicities. We designed and validated a tandem Fc-free tumor-specific 4-1BB agonist antibody fused to an engineered albumin sequence with high FcRn binding and favorable pharmacokinetics designed to confine 4-1BB costimulation to the tumor microenvironment. The antibody exhibited prolonged circulating half-life and in vivo tumor inhibition with no evidence of 4-1BB-associated toxicity when administered as purified protein or nucleoside-modified mRNA encoding the antibody.

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.