ZW1528, a bispecific blocker of IL-4Ra and IL-33, mediates simultaneous blockade of type 2 and non-type 2 inflammation characteristic for COPD. Broad blockade of two pathways results in improved control of inflammatory responses in vitro and in vivo compared to monospecific controls. Computationally driven sequence optimization and incorporation of half-life extending mutations further improved PK properties of IL-4Ra molecules, as exemplified by ZW1572, designed to co-block IL-4Ra and IL-31 for treatment of patients with atopic dermatitis.

XmAb412 is a half-life–extended bispecific antibody targeting TL1A and IL-23p19, key drivers of pathogenic T cell responses in IBD. This presentation will describe the discovery, engineering, and optimisation of XmAb412, as well as the discovery and development of XmAb942, a TL1A monospecific antibody currently in clinical evaluation. In vitro and in vivo data demonstrating potent activity and favourable pharmacokinetics, supporting the clinical development and best-in-class potential of both molecules, will be presented.

The molecular design of the sweeping antibody is a sophisticated, humanised biparatopic antibody for cytokine neutralisation, targeting two distinct epitopes on the cytokine antigen. It incorporates "target-sweeping" SMART-Ig technology with an engineered Fc region for improved recycling. In vitro assays demonstrate its potency in inhibiting monocyte migration, and in vivo non-human primate studies validate its mechanism of action, resulting in significantly reduced systemic levels of the free antigen.

IgE is a key mediator of allergic and atopic diseases, from common conditions such as asthma and atopic dermatitis to severe anaphylaxis. Seismic is targeting IgE via multiple approaches to rapidly disarm allergic effector cells by cleaving circulating IgE, dissociating IgE from effector cells and downmodulation of function, and sweeping IgE in the liver. This presentation will discuss these mechanisms and their potential to address unmet needs in IgE-mediated disease.

A strict gluten-free diet remains the primary management strategy for coeliac disease, despite its social cost and the difficulty of adhering to it. We describe an approach using engineered regulatory T cells (eTregs) expressing gluten-specific TCRs. eTregs suppressed gluten-reactive effector T cells in vitro and in vivo, including through bystander mechanisms. As eTreg therapies advance clinically in other indications, this strategy may offer a promising translational pathway for restoring tolerance in coeliac disease.

Leukocyte trafficking is targeted in Crohn's disease by blocking α4β7/MAdCAM-1 mediated travel of leukocytes to mucosal tissues in the gut. In an alternative approach we antagonise the cannabinoid receptor CB2R on leukocytes with a novel biologic miniprotein, effectively regulating expression of α4β7 and significantly reducing leukocyte trafficking to the gut. Detailed in vitro functional characterisation assays and preclinical studies of the mechanism of action in vivo will be presented here.

Cytokines are critical signalling molecules, but their therapeutic potential remains unrealised due to pleiotropic effects across cell types. Here we describe a simple, highly modular format called a Sterically Masked Activated Cytokine (SMACk), via facile assembly of a targeting Fab/VHH, cytokine, and Fc. We will describe the engineering strategy, mechanistic work, and functional data highlighting the application to multiple distinct cytokines.