Our single domain technology consistently demonstrates novel epitope targeting compared with VHHs and mAbs. We have explored multiple engineered constructs to exploit this plus other advantages of our platform to develop novel autoimmune and cancer products. I will discuss technology platforms, advantages, and exploitation of these through engineering in addition to sharing our in vivo disease model data on both inflammatory and oncology indications as we progress towards the clinic.

Intrabodies have significant biotherapeutic potential. However, challenges remain regarding development and delivery. Using a synthetic VHH phage display library and modified RNA, we developed VHH intrabodies that target the aberrant interactions between two intracellular calcium handling proteins in heart failure. We delivered these VHH intrabodies in vivo and expressed them specifically in the heart using Adeno-Associated Viral (AAV) transduction, resulting in improved cardiac function in a murine heart failure model.

Poor brain delivery is a major hurdle in the development of biological therapeutics for neurologic diseases because of poor Blood-Brain Barrier (BBB) penetration. Numerous brain shuttles based on single-domain VNAR antibodies were developed by Ossianix. These include TXP1, which was demonstrated to penetrate the brain with high efficiency when injected at a low therapeutic dose in non-human primates with an over 30-fold increase in comparison to the control.

Cysteine-rich miniproteins (knottins) have potential as therapeutic modulators of ion channels but suffer from manufacturing difficulties, short half-lives, and poor specificity. To overcome these challenges, Maxion has developed a novel antibody fusion format (KnotBodyÒ), wherein the antibody gains ion channel modulating capability of the knottin and the knottin enjoys the extended half-life, engineerability, and manufacturability of the antibody. This presentation illustrates the generation of KnotBody inhibitors of multiple ion channels and their optimisation using phage and mammalian display.

ConfoBodies stabilize a desired conformational state of a GPCR and enable conformation-directed drug screening and structure-guided elaboration. We will show the unique potential of ConfoBody stabilized GPCR conformations to facilitate de novo discovery of therapeutic antibodies exhibiting full agonist pharmacology to human GPCRs.

Ichnos’ BEAT platform (Bispecific Engagement by Antibodies based on the TCR) facilitates design of multispecific antibodies using efficient heavy chain heterodimerization and a common light chain. ISB 2001, a trispecific BCMA, CD38, and CD3-targeted T cell engager, was designed to enable high potency with low risk of on-target off-tumor toxicity and antigen sink effects. We will present the rational design of ISB 2001, exploring affinity of the three binding arms, avidity induction, as well as varying epitopes and architectures. ISB 2001 IND-enabling studies are ongoing, and a first-in-human study is expected to start in 2023.

Ensovibep is a multi-specific 5-domain DARPin therapeutic under development. Three domains cooperatively bind and block the SARS-CoV-2 spike protein receptor-binding domain; two domains bind HSA. In vitro pan-variant (incl. BA.2, BA.2) neutralisation activity has been demonstrated. Ph-1 and Ph-2a studies show favourable safety and viral load reduction (VLR). Ph-2b data from the EMPATHY randomised controlled trial show significant VLR and decreases in hospitalisation and death in ensovibep treated subjects.

Anticalins represent a class of small and stable therapeutic proteins that can be efficiently delivered to the lung and thus open new opportunities to treat various respiratory diseases locally. Accumulating preclinical and clinical data in asthma and idiopathic fibrosis suggest that these novel therapeutic interventions could help address unmet medical needs. The platform has further evolved with new bi-paratopic formats and tailor-suited developability assessments.

At Alchemab, we are harnessing the power of the immune system to counter complex diseases. Using a combination of next-generation sequencing, serum proteomics, and computational discovery we pinpoint antibodies associated with improved outcomes. Selected antibodies are characterized by their biological function and the targets which they bind. Many patient cohorts have been analyzed, across Neurodegeneration and Oncology, and antibodies to novel targets are progressing toward the clinic.

Inhibition of Ang2, resulting in Tie2 activation, is a clinically validated approach for the treatment of diabetic macular edema. Here we describe the discovery and optimization of a hexavalent direct Tie2 agonist and its physiological impacts in both mice and cynomolgus monkeys. We show the molecule resolves vascular leak in response to multiple inflammatory stimuli, including stimuli not addressable by approved agents, and that it has exposure and stability consistent with infrequent intravitreal administration.