Antibodies Against Challenging Targets

We describe the discovery and characterisation of CFTX-2034, a first-in-class agonist antibody targeting SSTR5, which plays a critical role in modulating GI motility, insulin, and incretin release. This offers a novel therapeutic approach for post-bariatric hypoglycemia, a serious complication of bariatric surgery that can lead to life-threatening hypoglycemic events. Its unique mechanism of action, robust preclinical efficacy, and long in vivo half-life position CFTX-2034 as a promising candidate for clinical development.

Maxion have shown that small cysteine-rich peptides (“knottins”) with ion channel-modulating activity can be inserted into antibody CDR loops while retaining their function. The resulting KnotBody molecules, modulate ion channel activity while benefitting from the optimal drug-like properties of antibodies. This presentation will illustrate the generation and optimisation of KnotBody inhibitors of Kv1.3, an important ion channel affecting function of T effector memory cells.

Peptide agonists targeting Class B1 GPCRs often lack clean receptor specificity, even as selective engagement is increasingly linked to differential efficacy and tolerability profiles. We describe an integrated discovery platform coupling AI-designed soluble GPCR analogues with mammalian display. Applied to the amylin receptor family, this approach yields agonists with exquisitely tunable subtype selectivity and function, all with the extended half-life enabled by the antibody format.

We have demonstrated that nanobodies targeting neurotransmitter receptors represent a promising new class of drugs for the treatment of brain disorders. We have developed nanobodies that target a class of glutamate receptors, the metabotropic glutamate (mGlu) receptors, which regulate synaptic transmission. We identified a nanobody capable of penetrating the brain that potentiates mGlu2 receptor activity. This nanobody restored behavioural deficits in two mouse models exhibiting symptoms of schizophrenia.

Lysosomal storage disorders with CNS involvement remain poorly addressed by conventional enzyme replacement therapies, which do not cross the blood-brain barrier at therapeutically meaningful levels. This presentation explores antibody-enabled approaches exploiting transferrin receptor–mediated transcytosis to shuttle therapeutic enzymes into the brain following peripheral administration. Key engineering considerations, translational challenges, and emerging early clinical evidence supporting receptor-mediated delivery platforms to transform treatment of neuronopathic lysosomal diseases will be discussed.

Bispecific soluble TCR engagers are a versatile therapeutic modality combining high-affinity targeting and off-the-shelf use. Initially developed to redirect T cell activation against tumours, this modality is also amenable to targeted T cell inhibition through clustering on tissue-specific targets followed by engagement of inhibitory receptors on T cells. Here we describe the engineering of highly specific, picomolar affinity TCRs designed to inhibit T cell activation in the skin.

At Alchemab Therapeutics we use our unique antibody discovery platform to find novel therapeutics for hard-to-treat diseases. Using patient samples, B cell sequencing, and computational analysis, we identify convergent protective antibody responses among individuals that are susceptible but resilient to specific diseases. We will present our pre-clinical candidate ATLX-PGDHi, a monoclonal antibody targeting the prostaglandin pathway, with potential as a first-in-class disease modifying therapy in Parkinson's disease.

The presence of suppressive immune cells such as regulatory T (Treg) cells are known to impair immunotherapy. Using a "Function-First" biopanning and functional screen followed by target deconvolution, we identified antibodies able to deplete Tregs and elicit tumour control in subcutaneous tumour models. From these, we identified a mAb binding a distinct epitope within ICAM-1 that unexpectedly mediates selectivity towards tumour Tregs. It demonstrated tumour control dependent on Fc?R-interaction and depletion of Tregs. We identified similar anti-human ICAM-1 clones. These data validate the target-agnostic discovery approach as a viable means to identify new therapeutic antibodies.

CB2 is a validated target for anti-inflammatory and anti-fibrotic therapies, but small-molecule development has been hindered by CB1 cross-reactivity. FAST, a library-scale functional selection platform, overcomes the difficulty of discovering GPCR agonist antibodies, yielding potent, selective CB2 agonists. Unlike current MASH treatments that address upstream metabolic dysregulation, CB2 agonist antibodies directly target downstream inflammation and reverse established fibrosis, providing a vital alternative for patients with limited options.