Autolus Therapeutics announces publication in Nature Communications 

Rhea-AI Summary

Autolus Therapeutics plc announces the development of TRBC1 and TRBC2-targeting immunotherapies for T cell lymphomas, introducing AUTO4 and AUTO5 CAR T cell therapies. Early clinical data from the LibraT1 study shows promising results. The publication in Nature Communications highlights the structural basis for selective CAR recognition of TRBC1 and TRBC2, paving the way for potential broad therapeutic approaches in T cell malignancies.

Oncology Doctor

The development of AUTO4 and the subsequent AUTO5 represents a significant advancement in the treatment of T cell malignancies. The therapeutic potential of CAR T cell therapies has been transformative in B cell lymphomas, but T cell lymphomas have historically been challenging due to the scarcity of suitable surface antigens that could be targeted without causing widespread immunosuppression. The differentiation between TRBC1 and TRBC2 in T cell lymphomas offers a unique therapeutic window. AUTO4's selective targeting of TRBC1 could potentially treat TRBC1 T cell lymphomas while preserving the normal TRBC2 compartment, which is crucial for maintaining immune function.

Furthermore, the early clinical data from the LibraT1 study is promising, suggesting that AUTO4 may be effective in relapsed/refractory T cell lymphoma. The ability to flip selectivity from TRBC1 to TRBC2 through in silico design and phage display, resulting in AUTO5, could broaden the therapeutic options for patients. These developments could change the clinical landscape for T cell malignancies, which have been underserved by current immunotherapy modalities.

Medical Research Analyst

The innovation in protein engineering demonstrated by Autolus in the development of AUTO5 from AUTO4 is noteworthy. The structural basis for the selective CAR recognition, highlighted by the ability to distinguish between TRBC1 and TRBC2 through a mere 2 amino acid inversion, is a testament to the precision of modern structural biology. This precision allows for the design of highly targeted therapies with potentially reduced off-target effects, a common concern in immunotherapies.

From a research perspective, the use of in silico design and phage display is a cutting-edge approach that accelerates the development of new therapeutics. The publication in Nature Communications underscores the scientific validity of the approach and adds to the credibility of Autolus' research. The broader implications for the field of immunotherapy are substantial, potentially leading to more refined and targeted treatments for a variety of malignancies beyond T cell lymphomas.

Biotech Financial Analyst

The progress reported by Autolus Therapeutics in the development of targeted CAR T cell therapies could have significant financial implications for the company and its investors. The targeting of T cell malignancies, a niche and previously difficult-to-treat area, opens up a market with unmet medical needs. The positive early clinical data for AUTO4 could be a precursor to potential regulatory approval and commercialization, which would be a major milestone for the company.

Investors should monitor the progress of AUTO5, as its development could provide a complementary therapeutic option, effectively doubling the company's addressable market within T cell malignancies. The novelty of the approach and the publication in a prestigious journal like Nature Communications may also attract partnership opportunities, licensing deals, or additional funding, which could positively impact the company's valuation and stock performance.

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.”

References:
1. Ferrari et al, Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies. Nat Commun 15, 1583 (2024) | doi: 10.1038/s41467-024-45854-3
2. Maciocia et al, Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies. Nat Med 23, 1416–1423 (2017) | doi: 10.1038/nm.4444
3. Cwynarski et al, First in human study of AUTO4, a TRBC1-Targeting CAR T cell therapy in refractory T cell lymphoma. Hematol Oncol 41, 80–81 (2023) | doi: 10.1002/hon.3163_44

About Autolus Therapeutics plc
Autolus is a clinical-stage biopharmaceutical company developing next-generation, programmed T cell therapies for the treatment of cancer and autoimmune disease. Using a broad suite of proprietary and modular T cell programming technologies, the Company is engineering precisely targeted, controlled and highly active T cell therapies that are designed to better recognize target cells, break down their defense mechanisms and eliminate these cells. Autolus has a pipeline of product candidates in development for the treatment of hematological malignancies, solid tumors and autoimmune diseases. For more information, please visit www.autolus.com.

Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are statements that are not historical facts, and in some cases can be identified by terms such as "may," "will," "could," "expects," "plans," "anticipates," and "believes." These statements include, but are not limited to, statements regarding Autolus’ development of its product candidates. Any forward-looking statements are based on management's current views and assumptions and involve risks and uncertainties that could cause actual results, performance, or events to differ materially from those expressed or implied in such statements. These risks and uncertainties include, but are not limited to, the risks that Autolus’ preclinical or clinical programs do not advance or result in approved products on a timely or cost effective basis or at all; the results of early clinical trials are not always being predictive of future results; the cost, timing and results of clinical trials; that many product candidates do not become approved drugs on a timely or cost effective basis or at all; the ability to enroll patients in clinical trials; and possible safety and efficacy concerns. For a discussion of other risks and uncertainties, and other important factors, any of which could cause Autolus’ actual results to differ from those contained in the forward-looking statements, see the section titled "Risk Factors" in Autolus' Annual Report on Form 20-F filed with the Securities and Exchange Commission, or the SEC, on March 7, 2023 and in Autolus' Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on November 9, 2023, as well as discussions of potential risks, uncertainties, and other important factors in Autolus' subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and Autolus undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise, except as required by law. You should, therefore, not rely on these forward-looking statements as representing Autolus’ views as of any date subsequent to the date of this press release.

Contact:  

Olivia Manser
+44 (0) 7780 471568 
o.manser@autolus.com

Julia Wilson 
+44 (0) 7818 430877 
j.wilson@autolus.com 

Susan A. Noonan 
S.A. Noonan Communications  
+1-917-513-5303   
susan@sanoonan.com 

Lauren Williams 
Investase 
+44 23 9438 7760 
lauren@investase.com  

What is the focus of Autolus Therapeutics plc's recent publication in Nature Communications?

The publication focuses on the development of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies.

What are the key differences between B cell lymphomas and T cell lymphomas in terms of immunotherapies?

Unlike B cell lymphomas, T cell lymphomas have not benefited from immunotherapies due to the lack of suitable surface target antigens.

What are the two types of TCRαβ targeted by Autolus in their therapeutic approaches?

Autolus targets TRBC1 and TRBC2, the two types of TCRαβ, in their therapeutic approaches.

What is the significance of AUTO4 in the treatment of T cell lymphomas?

AUTO4 is a CAR T cell therapy developed by Autolus that selectively targets TRBC1, potentially allowing for the treatment of TRBC1 T cell lymphomas while preserving the normal TRBC2 T cell compartment.

What is the potential of AUTO5 in the context of T cell malignancies?

AUTO5 is a TRBC2-specific CAR T cell therapeutic developed by Autolus, offering a broad therapeutic approach by exploiting TRBC1/2 TCR biology.