Human monoclonal antibodies specific for glypican-3 and use thereof
Inventors
Ho, Mitchell • Feng, Mingqian • Dimitrov, Dimiter S.
Assignees
US Department of Health and Human Services
Publication Number
US-9932406-B2
Publication Date
2018-04-03
Expiration Date
2032-04-19
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Abstract
Described herein is the identification of human monoclonal antibodies that bind GPC3 or heparan sulfate (HS) chains on GPC3 with high affinity. The antibodies described herein are capable of inhibiting HCC cell growth and migration. Provided are human monoclonal antibodies specific for GPC3 or HS chains on GPC3, including immunoglobulin molecules, such as IgG antibodies, as well as antibody fragments, such as single-domain VH antibodies or single chain variable fragments (scFv). Further provided are compositions including the antibodies that bind GPC3 or HS chains on GPC3, nucleic acid molecules encoding these antibodies, expression vectors comprising the nucleic acids, and isolated host cells that express the nucleic acids. Methods of treating cancer and/or inhibiting tumor growth or metastasis are also provided. Further provided are methods of detecting cancer in a subject and confirming a diagnosis of cancer in a subject.
Core Innovation
The invention relates to human monoclonal antibodies that specifically bind glypican-3 (GPC3) or heparan sulfate (HS) chains on GPC3 with high affinity. These antibodies include immunoglobulin molecules, such as IgG antibodies, as well as antibody fragments like single-domain VH antibodies or single chain variable fragments (scFv). The antibodies are capable of inhibiting hepatocellular carcinoma (HCC) cell growth and migration. They can be used in compositions for treatment, nucleic acid molecules encoding these antibodies, expression vectors, and host cells expressing these nucleic acids.
The antibodies and compositions provided are used for methods of treating cancer, inhibiting tumor growth or metastasis, as well as detecting cancer and confirming a diagnosis of cancer in a subject. Specifically, methods involve contacting a sample from a subject with antibodies that bind GPC3 or HS chains and detecting binding to confirm cancer presence or diagnosis. Treatment involves administering a therapeutically effective amount of these antibodies or immunoconjugates to subjects with GPC3-expressing cancers.
The problem addressed arises from the high prevalence and mortality of liver cancer, particularly HCC, which comprises about 75% of liver cancer cases. Traditional treatments like surgery have limitations, and chemotherapy is generally ineffective. There is a significant need for new drugs with different mechanisms of action, such as immunotherapy. However, immunotherapy development is challenged due to lack of good tumor-specific targets. GPC3 is an attractive target because it is highly expressed in HCC and some other cancers but not in normal tissues, although the precise biological roles of GPC3 in tumorigenesis were previously unknown.
Claims Coverage
The application includes independent claims covering chimeric antigen receptors (CARs), bispecific antibodies, and immunoconjugates comprising human monoclonal antibodies specific for GPC3, with detailed features of antibody regions and therapeutic agents.
Human variable heavy single-domain monoclonal antibody specific for glypican-3
Comprises a human VH single-domain monoclonal antibody that binds GPC3, including complementarity determining region (CDR) 1, 2 and 3 sequences of SEQ ID NO: 2, with CDRs determined by IMGT or Kabat numbering. The antibody may comprise residues 26-33, 51-57 and 96-105, or 31-35, 50-65 and 96-105 of SEQ ID NO: 2, or the full amino acid sequence of SEQ ID NO: 2.
Chimeric antigen receptors comprising the human monoclonal antibody
CARs comprising the human VH antibody binding GPC3 with CDRs of SEQ ID NO: 2, forming the targeting moiety for therapeutic use.
Bispecific antibodies comprising the human monoclonal antibody
Bispecific antibodies combining the human VH antibody that binds GPC3 with another binding moiety, comprising the CDRs or specified residues of SEQ ID NO: 2.
Immunoconjugates comprising the human monoclonal antibody linked to a therapeutic agent
Immunoconjugates comprising the human VH antibody that binds GPC3 with defined CDRs and a therapeutic agent such as a drug, including full-length or CDR-specific sequences from SEQ ID NO: 2.
The claims cover human VH single-domain antibodies specific for GPC3, their use in CARs, bispecific antibodies, and immunoconjugates with therapeutic agents, specifying antibody CDR sequences and residues per recognized numbering schemes, supporting therapeutic and diagnostic applications.
Stated Advantages
HN3 is a fully human single-domain antibody with high affinity that directly inhibits HCC cell proliferation, offering reduced immunogenicity and better tumor penetration compared to murine antibodies.
The single-domain nature of HN3 allows for ease of production and potential for engineering into bispecific antibodies, immunoconjugates, immunotoxins and engineered T cells.
HS20 specifically binds HS chains on GPC3 and inhibits HCC cell migration by blocking the interaction between GPC3 and Wnt3a, thereby interfering with Wnt signaling.
The antibodies enable specific targeting of GPC3-positive cancer cells with sub-nanomolar affinity, suitable for both therapeutic and diagnostic uses.
Documented Applications
Treatment of cancers expressing GPC3, including hepatocellular carcinoma (HCC), melanoma, lung cancer, and ovarian cancer, using human monoclonal antibodies or immunoconjugates.
Diagnostic detection and confirmation of cancer in subjects by contacting patient samples with the antibodies and detecting binding to GPC3 or HS chains on GPC3.
Use of human monoclonal antibodies in engineered cytotoxic T lymphocytes expressing chimeric antigen receptors targeting GPC3 for adoptive cancer therapy.
Generation of bispecific antibodies comprising GPC3-binding human monoclonal antibodies for immunotherapy by engaging T cells and tumor cells.
Anti-cancer immunotoxins comprising the single-domain antibody HN3 fused to Pseudomonas exotoxin for specific cytotoxicity to GPC3-expressing cancer cells in vitro and in vivo.
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