Compositions and methods for treating cancer with anti-CD19 immunotherapy

Inventors

Schneider, Dina • Orentas, Rimas J. • Dropulic , Boro • Dimitrov, Dimiter S. • Zhu, Zhongyu

Assignees

Lentigen Technology Inc • US Department of Health and Human Services

Abstract

Chimeric antigen receptors containing human CD19 antigen binding domains are disclosed. Nucleic acids, recombinant expression vectors, host cells, antigen binding fragments, and pharmaceutical compositions, relating to the chimeric antigen receptors are also disclosed. Methods of treating or preventing cancer in a subject, and methods of making chimeric antigen receptor T cells are also disclosed.

Core Innovation

The invention provides chimeric antigen receptors (CARs) containing human CD19 antigen binding domains, along with nucleic acids, recombinant expression vectors, host cells expressing these CARs, and pharmaceutical compositions related to these CARs. These CARs exhibit high surface expression on transduced T cells, a high degree of cytolysis of CD19-expressing cells, and demonstrate in vivo expansion and persistence when expressed in T cells. Methods of treating or preventing cancer using these CARs and methods of making CAR T cells are also disclosed.

Cancer presents significant treatment challenges, particularly because malignant tumors grow rapidly and metastasize, making treatment extremely difficult. Standard care for B-lineage leukemias involves high dose chemotherapy or radiation with associated high toxicity and risks such as relapse. While CD19 has been exploited as a target in antibody and CAR-T cell therapies, many binding moieties used in CAR constructs are derived from murine antibodies, which can lead to limited in vivo expansion of CAR+ T cells and rapid disappearance after infusion, resulting in disappointing clinical activity. Thus, there is an urgent need for novel compositions and methods to treat CD19-expressing B cell malignancies that demonstrate specific and efficacious antitumor effects while overcoming these shortcomings.

The innovation lies in the development of fully human anti-CD19 CARs that include antigen binding domains derived entirely from human sequences, which reduces immunogenicity and anti-CAR immune responses seen with murine-derived sequences. These human CARs exhibit superior properties, including higher surface expression, superior cytolytic activity, and increased in vivo persistence and expansion of CAR-T cells. The disclosed CAR constructs include a human anti-CD19 single chain variable fragment (ScFv) linked to a transmembrane domain and intracellular signaling domains such as 4-1BB and CD3 zeta. Affinity matured human anti-CD19 ScFv sequences have been generated and incorporated into CARs which have demonstrated specific and potent cytotoxicity and cytokine production in response to CD19-positive tumor cells. These improvements address the clinical challenges of CAR-T therapy for B cell malignancies and provide enhanced therapeutic alternatives.

Claims Coverage

The patent includes one independent claim focused on a method of treating CD19-expressing cancer using T cells expressing a specified chimeric antigen receptor. The inventive features relate to the specific CAR amino acid sequences encoded by the nucleic acids expressing the CARs with human CD19 antigen binding domains.

The claims primarily cover therapeutic methods of administering T cells expressing fully human anti-CD19 CARs with specified amino acid sequences to treat CD19-expressing cancers, specifically hematological malignancies and a range of adult carcinomas, highlighting the inventive CAR compositions encoded by the disclosed nucleic acids.

Stated Advantages

Documented Applications