Autolus Therapeutics announces publication in Nature Communications

LONDON, Feb. 22, 2024 (GLOBE NEWSWIRE) -- Autolus Therapeutics plc (Nasdaq: AUTL), a clinical-stage biopharmaceutical company developing next-generation programmed T cell therapies, today announces a publication in Nature Communications entitled: ‘Structure-Guided Engineering of Immunotherapies Targeting TRBC1 and TRBC2 in T Cell Malignancies.’¹

In contrast to B cell lymphomas, T cell lymphomas have not benefited from immunotherapies such as therapeutic antibodies or CAR T cell therapies. This is because suitable surface target antigens are lacking. Immunotherapies for B cell lymphomas target pan B cell antigens, however an equivalent strategy targeting pan T cell antigens would lead to unacceptable immunosuppression.

Nearly all T cell lymphomas express the αβ T-cell receptor (TCRαβ). There are two types of TCRαβ - TRBC1 and TRBC2. While normal T cells are a mixture of approximately 40% TRBC1 and 60% TRBC2, T cell lymphomas are clonal so entirely express either TRBC1 or TRBC2 exclusively. Autolus is developing therapeutic approaches which exploit this biology and has developed AUTO4, a CAR which selectively targets TRBC1². AUTO4 may allow for treatment of TRBC1 T cell lymphomas but should preserve the normal TRBC2 T cell compartment, preventing immunosuppression. Early clinical data from the LibraT1, a study of AUTO4 in patients with relapsed/refractory T cell lymphoma has been presented.³

The targetable difference between TRBC1 and TRBC2 is very small – merely a 2 amino acid inversion. In this publication, the research team at Autolus first describe the structural basis for selective AUTO4 CAR recognition of TRBC1. This structure shows that some amino acid residues stabilize the interaction with the TCR generally, while others result in selectivity. By exploiting this structure, the research team used in silico design and phage display to flip selectivity of the AUTO4 binder from TRBC1 to TRBC2 to generate AUTO5, a TRBC2-specific CAR T cell therapeutic.

“The development of a TRBC2-specific therapeutic by in silico design is a tour-de-force of structural biology and protein engineering from the research team at Autolus,” said Dr Martin Pule Chief Scientific Officer and founder of Autolus. “T cell malignancies are a neglected clinical area and the development of AUTO5 along with AUTO4 could allow us to develop a broad therapeutic approach that exploits TRBC1/2 TCR biology.”