Glypican-3 antibody and uses thereof
Inventors
Assignees
University of Pennsylvania Penn • US Department of Veterans Affairs
Publication Number
US-10093746-B2
Publication Date
2018-10-09
Expiration Date
2035-09-03
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Abstract
The present invention relates to compositions and methods of isolated polynucleotides that encode or polypeptides comprising glypican-3 (GPC3). The invention also includes a chimeric antigen receptor (CAR) wherein the CAR is able to target GPC3. The invention further includes methods of treating a subject or diagnosing and treating diseases, disorders or conditions associated with dysregulated glypican-3.
Core Innovation
The invention relates to compositions and methods involving isolated polynucleotides that encode polypeptides comprising glypican-3 (GPC3). It includes a chimeric antigen receptor (CAR) capable of targeting GPC3, as well as methods of treating subjects or diagnosing and treating diseases, disorders or conditions associated with dysregulated glypican-3.
The background identifies hepatocellular carcinoma (HCC) as a major cancer with high mortality. GPC3 is re-expressed at high frequency in neoplastic hepatocytes and serves as a useful diagnostic biomarker and immunohistochemical test. Glypican-3's role includes association with growth factors and possible immunomodulatory function. Inhibition of GPC3 negatively affects HCC proliferation. Unlike other tumor antigens, GPC3 is a membrane-associated protein with a large extracellular domain suitable for antibody-directed therapy. However, GPC3-specific T cell therapies and GPC3-specific single chain variable fragment antibodies (scFv) are under development. This invention addresses the need for GPC3-specific antibodies and CARs.
The summary outlines aspects of the invention comprising isolated polynucleotides encoding anti-GPC3 antibodies or fragments, isolated anti-GPC3 polypeptides comprising heavy and light chains with specified sequences, pharmaceutical compositions with these components, isolated nucleic acid sequences encoding CARs comprising a GPC3 binding domain, transmembrane domain, costimulatory signaling region, and CD3 zeta signaling domain. The invention also includes T cells expressing these CARs, methods of imaging or diagnosing GPC3-associated conditions, methods of inhibiting growth of GPC3-expressing tumor cells, and methods of treating diseases associated with dysregulated GPC3, including liver cancer. Various embodiments specify antibody fragment types and co-stimulatory domains.
Claims Coverage
The claims include eight independent claims defining isolated polynucleotides encoding anti-GPC3 antibodies, isolated anti-GPC3 antibodies, isolated nucleic acid sequences encoding CARs targeting GPC3, isolated CAR molecules, and genetically modified T cells expressing these CARs. The claims cover compositions, diagnostic methods, therapeutic methods, and CAR components.
Isolated polynucleotide encoding anti-GPC3 antibody
An isolated polynucleotide encoding an anti-GPC3 antibody or antigen-binding fragment comprising a heavy chain variable region with SEQ ID NO: 1 and a light chain variable region with SEQ ID NO: 3.
Isolated anti-GPC3 antibody or antigen-binding fragment
An isolated anti-GPC3 antibody or antigen-binding fragment comprising a heavy chain variable region with SEQ ID NO: 2 and a light chain variable region with SEQ ID NO: 4, with antigen-binding fragments selected from Fab, F(ab')2, Fv, and single chain Fv (scFv).
Method of imaging or visualizing tissue with labeled anti-GPC3 antibody
A method of imaging or visualizing a sample from normal or malignant tissue by contacting the sample with a labeled anti-GPC3 antibody or fragment comprising the specified heavy and light chain variable regions.
Method of inhibiting growth of GPC3-expressing tumor cell
A method of inhibiting growth of a GPC3-expressing tumor cell by contacting it with the isolated anti-GPC3 antibody or antigen-binding fragment described with specific heavy and light chain sequences.
Pharmaceutical compositions comprising isolated polynucleotide or antibody
Pharmaceutical compositions comprising an effective amount of the isolated polynucleotide encoding the anti-GPC3 antibody or the isolated anti-GPC3 antibody/fragment.
Isolated nucleic acid sequence encoding a CAR targeting GPC3
An isolated nucleic acid sequence encoding a CAR comprising a GPC3 binding domain (encoded by SEQ ID NOs: 1 and 3), a transmembrane domain, a costimulatory signaling region (from defined costimulatory molecules), and a CD3 zeta signaling domain.
Isolated CAR molecule with GPC3 binding domain and signaling domains
An isolated CAR comprising a GPC3 binding domain (SEQ ID NO: 2 and 4), a CD3 zeta signaling domain, optionally a costimulatory signaling domain from specified costimulatory molecules, and wherein the GPC3 binding domain can be a humanized antibody or fragment such as Fab or scFv.
Genetically modified T cell expressing the CAR
A T cell genetically modified to comprise the isolated nucleic acid sequence encoding the CAR described above.
Method of providing anti-tumor immunity using genetically modified T cells
A method of providing anti-tumor immunity by administering genetically modified T cells expressing a CAR with GPC3 binding domain, 4-1BB co-stimulatory domain, and CD3 zeta signaling domain, where the T cell is autologous and the subject is human.
Method of treating GPC3-expressing liver cancer with CAR T cells
A method of treating liver cancer expressing GPC3 by administering genetically modified T cells expressing a CAR with GPC3 binding domain, 4-1BB co-stimulatory domain, and CD3 zeta signaling domain.
The claims encompass isolated polynucleotides and antibodies specific to GPC3 with defined heavy and light chain sequences, CAR constructs incorporating GPC3 binding domains with signaling domains, genetically modified T cells expressing these CARs, pharmaceutical compositions comprising these components, and methods of diagnosis, imaging, tumor cell growth inhibition, anti-tumor immunotherapy, and treatment of GPC3-expressing cancers, particularly liver cancer.
Stated Advantages
GPC3 is a membrane-associated protein with a large extracellular domain making it attractive for antibody-directed therapy.
Antibodies specific to GPC3 can be used for diagnostic and therapeutic applications, including immunotherapy of cancers such as hepatocellular carcinoma.
The CAR T cells directed against GPC3 exhibit potent cytolytic activity, cytokine secretion, tumor infiltration, and anti-tumor effects both in vitro and in vivo.
The fully-human CAR-modified T cells show resistance to soluble GPC3 inhibition, mediate bystander killing, and mediate regression of established human tumors.
CAR-modified T cells have the ability to replicate and persist long-term in vivo, leading to sustained tumor control.
Documented Applications
Diagnosis and prognosis of diseases associated with GPC3 expression, such as liver cancer, by detecting GPC3 via antibodies.
Imaging or visualization of samples from normal or malignant tissues, including liver tissue, using labeled anti-GPC3 antibodies or fragments.
Treatment methods for inhibiting growth of GPC3-expressing tumor cells using anti-GPC3 antibodies or fragments.
Methods of providing anti-tumor immunity and treating cancers, including hepatocellular carcinoma, pancreatic cancer, ovarian cancer, stomach cancer, lung cancer, and endometrial cancer, via administration of genetically modified T cells expressing GPC3-targeting CARs.
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