Compositions and methods for targeting CD13 and TIM-3 with CAR T cells to treat acute myeloid leukemia
Inventors
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Assignees
University of Pennsylvania Penn
Member
University of Pennsylvania (Penn)The University of Pennsylvania (Penn), founded in 1740 by Benjamin Franklin, is a world-renowned Ivy League institution located in Philadelphia. Penn is dedicated to advancing knowledge, fostering innovation, and making a positive impact locally and globally. With a strong commitment to interdisciplinary research, academic excellence, and community engagement, Penn offers a diverse and inclusive environment for students, faculty, and staff. The university is recognized for its leadership in research, robust financial aid programs, and a tradition of civic involvement. Penn's strategic initiatives, such as Penn Forward, focus on reshaping education, research, and service to meet the challenges of a rapidly changing world. The university is also a leader in sustainability, aiming for carbon neutrality by 2042 and net-zero endowment emissions by 2050, and is home to a vibrant ecosystem of innovation, global engagement, and community partnership.
The University of Pennsylvania (Penn), founded in 1740 by Benjamin Franklin, is a world-renowned Ivy League institution located in Philadelphia. Penn is dedicated to advancing knowledge, fostering innovation, and making a positive impact locally and globally. With a strong commitment to interdisciplinary research, academic excellence, and community engagement, Penn offers a diverse and inclusive environment for students, faculty, and staff. The university is recognized for its leadership in research, robust financial aid programs, and a tradition of civic involvement. Penn's strategic initiatives, such as Penn Forward, focus on reshaping education, research, and service to meet the challenges of a rapidly changing world. The university is also a leader in sustainability, aiming for carbon neutrality by 2042 and net-zero endowment emissions by 2050, and is home to a vibrant ecosystem of innovation, global engagement, and community partnership.
Publication Number
US-12383581-B2
Publication Date
2025-08-12
Expiration Date
Abstract
The present invention includes compositions and methods for treating AML utilizing bispecific CARs. In certain aspects, the invention includes a bispecific split CAR which binds CD13 and TIM-3 on AML cells.
Core Innovation
The present invention includes compositions and methods for treating acute myeloid leukemia (AML) utilizing bispecific CARs, for example bispecific split CARs which bind CD13 and TIM-3 on AML cells. The invention addresses the need for novel approaches for improving CAR T cell-mediated AML therapy by providing CAR constructs and related compositions that target AML-specific surface targets.
As described, the invention provides bispecific chimeric antigen receptors comprising a first antigen binding domain capable of binding CD13, a first intracellular domain, a second antigen binding domain capable of binding TIM-3, a transmembrane domain, and a second intracellular domain, and further provides inducible bispecific CARs, TIM-3-specific CARs, modified T cells or precursors comprising such CARs, nucleic acids encoding such CARs, and methods for treating cancer, including AML, by administering modified T cells comprising the CARs.
Claims Coverage
One independent claim is present. The claim recites five main inventive features related to the bispecific CAR composition.
First antigen binding domain (CD13, SEQ ID NO: 1)
A first antigen binding domain capable of binding CD13, wherein the first antigen binding domain comprises the amino acid sequence set forth in SEQ ID NO: 1.
Second antigen binding domain (TIM-3)
A second antigen binding domain capable of binding TIM-3.
First intracellular domain
A first intracellular domain as a component of the bispecific CAR.
Second intracellular domain
A second intracellular domain as a component of the bispecific CAR.
Transmembrane domain
A transmembrane domain as a component of the bispecific CAR.
The independent claim covers a bispecific chimeric antigen receptor composed of a CD13-binding antigen binding domain (SEQ ID NO:1), a TIM-3-binding antigen binding domain, a transmembrane domain, and two intracellular domains.
Stated Advantages
Provides the specificity needed to target the AML tumor while sparing HSCs and the healthy myeloid compartment of the hematopoietic system.
Bispecific and split CARs more potently kill leukemic stem cells (LSCs) which express both TIM-3 and CD13, but spare normal HSCs which express CD13 but not TIM-3.
Reduced toxicity to human HSCs in vivo compared to conventional CD13-targeting CARs.
An inducible (switchable) bispecific CAR provides controllable activation such that T cells can be fully activated only by LSCs but not by HSCs.
Documented Applications
Treating acute myeloid leukemia (AML) by administering a modified T cell or precursor comprising a bispecific CAR that binds CD13 and TIM-3.
Adoptive cell transfer therapy/immunotherapy compositions comprising modified T cells expressing the disclosed CARs, including methods comprising administering modified T cells to a subject in need thereof.
Treatment of cancer more broadly, with the specification listing multiple cancer types as applications for the modified immune cells or methods, including leukemias, lymphoid malignancies, carcinomas, sarcomas, melanomas, solid tumors, and examples such as pancreatic neuroendocrine tumors, gastrointestinal NETs, lung and prostate NETs, breast cancer, ovarian cancer, and others explicitly enumerated in the document.
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