A T cell clone that recognises the most common KRAS mutation, KRASG12D, presented as a peptide by HLA-A11, was isolated from PBMCs. The affinity of the TCR was enhanced a million-fold and demonstrated remarkable ability to distinguish between KRASG12D and KRASWT peptides. ImmTAC molecules were generated; the binding selectivity translated into biological specificity, redirecting T cell cytotoxicity towards KRASG12D presenting colon cancer cells while sparing normal colon epithelial cells.

TCEs are multi-specific molecules typically binding the CD3/TCR complex and a specific tumor membrane antigen, triggering (MHC)-independent cancer cell elimination. NANOBODY molecules are engineered proteins derived from “heavy chain” antibodies that can be connected like beads on a string creating highly developable new multi-valent and multi-specific compounds. An example of a NANOBODY-based TCE will be presented.

A new generation of engineered fusion proteins is currently being developed to enhance endogenous and synthetic immunity approaches for cancer immunotherapy. The talk will cover both a PD-1-cis-targeted IL-2 variant used to differentiate antigen-specific, stem-like T cells into better effectors and also the combination of tumor-targeted costimulatory receptor agonists with T cell engaging bispecific antibodies as an off-the-shelf approach for enhanced T cell redirection. Both of these approaches are currently being tested in first-in-class clinical trials.

Antibody-based immunotherapy is a promising strategy in cancer treatment. IgG eliminates tumor cells through NK cell-mediated ADCC and macrophage-mediated antibody-dependent phagocytosis. Neutrophils have been largely overlooked as potential effector cells because IgG ineffectively recruits neutrophils. By contrast, IgA potently activates neutrophils and induces migration through FcaRI. IgA has however poorer half-life and does not activate NK cells. Bispecific antibodies targeting FcaRI combine the best of both worlds and will be discussed.

The discovery of appropriate targets and epitopes remains a bottleneck to developing antibody-based therapeutics, such as bispecific cell engagers and ADCs. Atreca’s Immune Repertoire Capture® (IRC™) platform identifies tumor-selective antibodies directly from patients experiencing active immune responses. Target- and epitope- identification for Fvs emerging from Atreca’s target-agnostic approach will be presented. In particular EphA2 and glycan binders, and the yeast-display and CRISPR tools applied in these cases, will be highlighted. 

We have developed human and human-like antibodies against several infectious diseases and toxins (e.g. diphtheria toxin, botulinum toxins, VEEV, WEEV, Marburg virus, Ebola virus). In the last few years, we have focused our antibody and biomarker development on infectious diseases and have developed a unique repertoire of neutralizing and protective human antibodies using our phage display development pipeline. In this presentation several examples from our infectious diseases pipeline will be presented.

Anticalin proteins are a novel class of biotherapeutics which, based on their biophysical properties and small size of approximately 20 kDa, are particularly well-suited for delivery via inhalation. Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and ultimately fatal lung disease lacking well-tolerated and effective therapies. We will describe the preclinical development of the inhaled Anticalin protein PRS-220 that targets connective tissue growth factor (CTGF), a driver of fibrotic lung remodeling, as a novel and promising inhaled therapy for IPF.

The CRUK AstraZeneca Antibody Alliance collaborates with the oncology academic community to discover novel medicines for cancer patients. Here we will describe how we find and validate novel ADC targets for cancer. The presentation will walk through the discovery of putative targets by AI collaborations and move on to discuss the key experiments required to build enough confidence to deliver an ADC therapeutic campaign.

This talk will describe the discovery and biological characterization of GSK6097608 which targets the inhibitory immune receptor CD96. We used the yeast-based Adimab platform for rapid discovery and subsequent selection of higher affinity variants. GSK6097608 can block CD155 binding and compete off bound CD155 from CD96. We explored different Fc regions and demonstrated that wild-type Fc is required for its activity and showed Fc-dependent potentiation of both primary human T and NK cells. CD96 is part of the CD226 axis which plays a role in regulating NK and T cells in tumor immunology.