Antibodies with immune effector activity and that internalize in folate receptor alpha-positive cells

Inventors

Nicolaides, Nicholas C. • Grasso, Luigi • Sass, Philip M.

Assignees

Eisai Inc

Abstract

This invention relates to the use of monoclonal and polyclonal antibodies that specifically bind to and have the ability in the alternative to become internalized by cells expressing folate receptor alpha (FRA) and to induce an immune effector activity such as antibody-dependent cellular cytotoxicity. The antibodies are useful in specific delivery of pharmacologic agents to FRA-expressing cells as well as in eliciting an immune-effector activity particularly on tumor cells and precursors. The invention is also related to nucleotides encoding the antibodies of the invention, cells expressing the antibodies; methods of detecting cancer cells; and methods of treating cancer using the antibodies.

Core Innovation

The document describes “in-out” folate receptor alpha (FRA)-binding antibodies that alternatively elicit immune effector activity or internalize into FRA-positive cells. The antibodies bind FRA and are used in association with conjugates, where antibody internalization supports targeted delivery into FRA-positive cancer/dysplastic cells. The document further describes antibody formats and derivatives including chimeric, humanized, and fully human antibodies, as well as polynucleotides encoding the antibodies and cells producing them.

The problem addressed is that previous FRA antibodies have limitations, including poor internalization and/or insufficient effector function. The document relates FRA expression to cancers, notably ovarian cancer, and positions improved FRA-binding antibody behavior combining immune effector activity with internalization against these limitations. The described “in-out” concept connects FRA binding with either immune effector activity such as ADCC/CDC or internalization for targeted delivery.

In the illustrative material, an FRA-specific monoclonal antibody such as ML-1 is described as showing FRA binding, robust ADCC against FRA-expressing ovarian cancer cells, and internalization into FRA-positive cells using an immunotoxin or conjugate format. The document additionally references other antibodies such as LK26 and MOv18 and includes an antibody produced by cells having ATCC accession number PTA-7552. The disclosed therapeutic concept includes combining the antibody produced by PTA-7552 with doxorubicin for treating FRA-positive ovarian cancer in a subject in need of treatment.

Claims Coverage

The partial content contains one independent claim directed to treating folate receptor-alpha-positive ovarian cancer and using an antibody produced by cells assigned ATCC accession PTA-7552 together with doxorubicin. The claim set includes dependent claims that narrow the antibody format to humanized, restrict the subject to humans, and specify antibody administration by injection or infusion.

Across the independent claim and dependents in the provided claim text, the core inventive coverage is therapeutic treatment of folate receptor-alpha-positive ovarian cancer by co-administering doxorubicin with an antibody produced by cells assigned ATCC accession PTA-7552, with further limiting features specifying humanized antibody, a human subject, and administration by injection or infusion.

Stated Advantages

Documented Applications

No documented applications found