G protein-coupled receptors (GPCRs) are the largest class of cell surface drug targets which play central roles in regulating many cellular and physiological processes. We present structures of a family A GPCR in both the inactive, antibody-bound, and the active, ligand-bound state. Our structures elucidate a novel ligand-mediated activation mechanism and shed light on the molecular mechanisms of GPCR-ligand recognition and antibody-mediated inhibition, potentially facilitating therapeutic intervention on this target.

Targeted protein degradation is an emerging concept for regulating challenging membrane drug targets. Unlike traditional antibody approaches, targeted degradation methods do not rely on neutralizing binders. This presentation introduces a new protein degradation technology based on multi-specific antibodies. This novel molecular archetype is highly effective in degrading various types of membrane proteins, including single-pass, multi-pass, native, or synthetic receptors, with a degradation efficiency of over 90% in various cellular systems.

Multi-pass transmembrane proteins represent some of the most important drug target classes across a wide range of therapeutic areas. An update on antibody-based therapeutics in the GPCR, ion channel, and transporter R&D pipeline will be provided outlining the breadth and diversity of the target landscape.

DJS Antibodies is a biotech company focused on discovery of antibodies to GPCRs, aiming to develop treatments for inflammatory and fibrotic diseases. In October 2022, we joined AbbVie, Inc., where we are expanding on this core mission while acting as AbbVie’s first UK research site. In this talk we will share our experiences discovering and developing the first monoclonal antibody inhibitor of LPAR1, a clinically-validated target for fibrotic disease.

Discovering therapeutic antibodies against multi-span membrane proteins, such as GPCRs and ion channels, remains a formidable challenge primarily due to poor antigen quality. The EMP technology can remove roadblocks for the most challenging targets, by enabling use of the whole target protein with properly folded transmembrane domains to be employed in discovery campaigns. Case studies will be shown where antibody hits with high affinity, selectivity, and developability were identified.

i-bodies are small, stable, human scaffolds inspired by the shark single domain antibodies. AD-214 is an i-body with affinity for CXCR4, a GPCR which is known to be upregulated in one cancer and several fibrotic conditions. AD-214 has anti-fibrotic activity in several preclinical models of fibrosis and has been found to be safe in a first in human clinical trial. The i-body platform has potential in several other disease modalities.

We have developed a fusion protein technology to enable the direct incorporation of multi-pass membrane proteins into the membrane of two antigenically distinct poxviruses. The protein of interest is correctly folded and expressed in the cell-derived viral membrane and does not require any detergents or refolding before downstream use. Antigen expressing virus can be readily purified and used for antibody selection using any in vitro display platform or for immunization and ex vivo antibody discovery. We will describe the use of this technology to discovery high-affinity functional antibodies specific for CXCR5 and other multi-pass membrane proteins. 

At Antiverse, we have developed an Artificial Intelligence (AI)-powered de novo antibody discovery platform, which designs antibody candidates against difficult-to-drug targets, including GPCRs and ion channels. Computational methods offer strong advantages over traditional antibody discovery methods. Through a combination of machine learning to design target-specific antibody libraries and hyper-expressing cell lines expressing abundant epitope, we facilitate the generation of diverse antibody candidates, with enhanced affinity, specificity, and improved therapeutic potential.

Recent studies have suggested a potential link between MC1R and autoimmune diseases. However, the lack of selective tools has slowed down the development of new drugs. We will discuss how we have identified very selective, high-potent MC1R agonist biologics using Confo’s proprietary technology to lock GPCRs in the active state, and how these exhibit anti-inflammatory activity in a preclinical in vivo model.

Delivering antigens/immunogens for biologics discovery against challenging membrane targets is often a bottleneck in the discovery process. At GSK we have successfully employed both novel genetic and biochemical approaches, through an enabling platform, to deliver membrane proteins for Ab discovery programs. I would like to present our success stories and key learnings from this exercise, highlighting the improvement in cycle times, thereby allowing early start to screening campaigns.

Complex cellular targets such as G protein-coupled receptors (GPCRs) and other multi-transmembrane proteins represent a significant challenge for therapeutic antibody discovery, primarily because of poor stability of the target protein upon extraction from cell membranes. I will present the strategy we used to discover a GPCR biologic with optimized potency, PK, and biophysical characteristics and will also discuss the criticality of antigen design strategy to connect affinity maturation to potency improvements.

CorA is a homopentameric magnesium channel in prokaryotes, and undergoes a series of asymmetric ion-dependent conformational transitions leading to activation. In order to thoroughly characterize these transitions, we determined a panel of conformation-specific synthetic antibodies against CorA using competitive selections and a robust phage display platform for membrane protein antibody discovery. This work offers a case study on trapping functional states of membrane proteins for both basic and applied research.

Antibody drug campaigns against challenging targets often lead to non-developable antibodies. Failures are associated with (i) the high biological target complexity of ion channels, GPCRs, and SLC transporters, (ii) low library quality, and (iii) display and screening technologies unfit for non-controlled conditions. Here, case studies of highly stable and conformation-specific antibodies are presented using the smart library design and novel technology of Linkster discovery platform.

Monocarboxylate transporter 1 (MCT1) is a membrane protein that transports lactate and is required for effector functions of activated immune cells. Blocking lactate transport has a potential therapeutic benefit for treating a wide number of autoimmune diseases. To address this unmet need we developed an anti-human MCT1 mAb that blocks solute transport (lactate efflux) from activated lymphocytes. This first-in-class inhibitor represents a new class of drugs to treat autoimmune diseases.