Human monoclonal antibodies specific for glypican-3 and use thereof

Inventors

Ho, Mitchell • Feng, Mingqian • Dimitrov, Dimiter S. • Gao, Wei

Assignees

US Department of Health and Human Services

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 provides 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 including single-domain VH antibodies and single chain variable fragments (scFv). Compositions comprising these antibodies, nucleic acid molecules encoding them, expression vectors, and host cells expressing these nucleic acids are also described. The antibodies can be conjugated to effector molecules, such as toxins, to form immunoconjugates for therapeutic purposes.

The antibodies and compositions are useful for treating cancers, notably hepatocellular carcinoma (HCC), by inhibiting tumor growth and metastasis, and for detecting or confirming cancer expressing GPC3 in subjects. Methods include administering a therapeutically effective amount of GPC3- or HS-specific antibodies or immunoconjugates to subjects with GPC3-expressing cancers. Also disclosed are diagnostic methods whereby samples from subjects are contacted with these antibodies to detect GPC3 presence, aiding cancer diagnosis or confirmation.

The problem addressed arises from the limited treatment options for liver cancer, especially HCC, which is prevalent and exhibits poor response to chemotherapy. Immunotherapy is challenged by the scarcity of suitable tumor-specific targets. GPC3 is highly expressed in HCC and some other cancers but not in normal tissues, making it a tumor-specific target. Prior studies showed that soluble GPC3 inhibits HCC cell proliferation, but the precise biological role of GPC3 and approaches to target it therapeutically were not established. This invention provides fully human monoclonal antibodies that specifically bind GPC3 or its HS chains, offering new mechanisms to inhibit HCC growth and migration, addressing the urgent need for novel therapeutics and diagnostic tools.

Claims Coverage

The patent includes multiple independent claims that focus on a human VH single-domain monoclonal antibody specific for GPC3, compositions containing the antibody or immunoconjugates, and methods of treatment, diagnosis, and inhibition of tumor progression using such antibodies.

The claims cover isolated human VH single-domain antibodies specific for GPC3, their pharmaceutical compositions, immunoconjugates with toxins such as PE38, methods for cancer treatment and detection using these antibodies, and nucleic acid constructs encoding the antibodies for expression in host cells.

Stated Advantages

Documented Applications