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

Inventors

Grasso, Luigi • Nicolaides, Nicholas C. • 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 invention relates to in-out anti–folate receptor alpha (FRA) antibodies that bind FRA-positive cells and alternatively elicit immune effector function and internalize upon binding. By binding FRA-positive cells, the antibodies enable immune killing through antibody-dependent cellular cytotoxicity and/or complement-dependent cytotoxicity, and they support targeted delivery of conjugated agents through internalization.

The invention is directed to therapeutically using FRA-binding antibodies in cancers in which FRA is expressed, including ovarian cancer and other FRA-positive cancers. The document describes antibody forms including chimeric, humanized, fully human, and antibody fragments, as well as variants, and discusses binding and immune function confirmation concepts such as ELISA/FACS and assays for ADCC and internalization.

A specific example antibody is described as the antibody produced by cells having American Type Culture Collection accession number PTA-7552, including an example monoclonal antibody (ML-1). Example data described in the document indicate binding to FRA and ADCC activity, and internalization is demonstrated in connection with immunotoxin killing, illustrating the dual function of immune effector elicitation and internalization for FRA-positive cell targeting.

The document further describes therapeutic conjugation concepts for FRA-positive cell targeting using conjugated agents, including toxins, radioisotopes, chemotherapeutics, and antifolates. Detection methods for FRA-positive cells are described, supporting identification of FRA-positive targets for the in-out antibody approach.

Claims Coverage

This family includes one independent claim focused on treating FRA-positive ovarian cancer by administering gemcitabine together with an antibody produced by cells having ATCC accession number PTA-7552, totaling 1 independent claim with 2 core inventive combination elements.

Across the independent claim, the claim coverage centers on combining a therapeutically effective amount of gemcitabine with a therapeutically effective amount of a specific PTA-7552-produced FRA-targeting antibody for treatment of FRA-positive ovarian cancer. Dependent claims refine the antibody to a humanized form, specify a human subject, and narrow antibody administration to injecting or infusing.

Stated Advantages

Documented Applications