A CD1c lipid agnostic T cell receptor bispecific engager redirects T cells against CD1c + cells

Rita Szoke-Kovacs¹Sophie Khakoo¹Victor Lopes Rangel¹Pietro Dellacristina¹Johanne Pentier¹Rahul Khanolkar¹Sam El-Ajouz¹Robert Simmons¹David K Cole¹Peter Gogolak²Mariolina Salio^1*Vijaykumar Karuppiah^1*

• ¹Immunocore (United Kingdom), Abingdon, United Kingdom
• ²University of Debrecen, Debrecen, Hajdu-Bihar, Hungary

Immunotherapy is emerging as an efficacious treatment for some cancers, complementing traditional chemo-radiation therapies. Specific markers at the cell surface of cancer cells can be used as immunotherapy targets. However, many of these markers are defined by a patient's genetic background, limiting their use across the human population. Here, we investigated the non-polymorphic antigen presenting molecule, CD1c, that is only expressed on subsets of mature hematopoietic cells, as a potential immunotherapy target with reduced risk of off-tumor on-target toxicity in healthy tissues. By phage display, we identified a T cell receptor (TCR) which recognises CD1c in a lipid independent manner and determined the crystal structure of the TCR-CD1c complex which revealed flexibility around the lipid binding region, and a new binding mechanism of auto-antigen recognition. We generated affinity enhanced variants of the TCR and fused them to an anti-CD3 antibody for T cell redirection. Lipidomic analysis revealed promiscuous lipid recognition of CD1c by the affinity enhanced TCR variants, with preference for larger lipid head group, a finding which is supported by the crystal structure. The bispecific molecule induced potent redirected T cell killing of CD1c positive cell lines. These proof-of-concept findings demonstrate that CD1c targeting TCR bispecific engagers might be good candidates for the development of non-MHC restricted, universal therapeutics for the treatment of CD1c + leukemias.