Monoclonal antibodies that specifically block biological activity of a tumor antigen

Inventors

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

Assignees

Eisai Inc

Abstract

This invention relates to novel monoclonal antibodies that specifically bind to the alpha-folate receptor. In some embodiments, the antibodies inhibit a biological activity of folate receptor-α (FR-α). The antibodies are useful in the treatment of certain cancers, particularly cancers that have increased cell surface expression of the alpha-folate receptor (“FR-α”), such as ovarian, breast, renal, colorectal, lung, endometrial, or brain cancer. The invention also relates to cells expressing the monoclonal antibodies, antibody derivatives, such as chimeric and humanized monoclonal antibodies, antibody fragments, and methods of detecting and treating cancer using the antibodies, derivatives, and fragments.

Core Innovation

The invention relates to monoclonal antibodies that specifically bind folate receptor-alpha (FR-α) and preferentially recognize multimeric, including tetrameric, FR-α on tumor cells. The antibodies block FR-α biological activity by targeting a tumor-associated multimer formation state rather than monomeric FR-α. The disclosed antibodies have an epitope distinct from LK26, and the multimeric binding is disulfide-dependent.

The disclosure provides antibody characteristics including higher affinity, competition versus LK26, and disulfide-dependent epitopes. It also describes specific heavy chain and light chain sequences and nucleic acid encodings using SEQ ID NOs, with the epitopes and binding behavior supporting selective recognition of tetrameric FR-α. The antibody compositions are described as therapeutics with functional potential.

The disclosed compositions are stated to be purified and formulated as ADCC-capable therapeutics. Experimental support described in the disclosure includes binding affinity measurements using surface plasmon resonance, Western blot evidence for tetrameric FR-α recognition versus monomeric recognition, and ADCC killing comparisons to control IgG. The disclosure also includes immunohistochemistry tissue binding specificity with cancer-enriched staining and in vivo xenograft growth inhibition metrics.

Claims Coverage

The provided independent claim set consists of two independent claims that define antibody-containing compositions against folate receptor-alpha using specified heavy and light chain sequence definitions and a composition exclusion regarding a specified polypeptide segment, for a total of three core inventive elements across the independent claims.

Across the independent claims, the inventive coverage is directed to compositions containing an FR-α specifically binding antibody with defined heavy and light chain sequence assignments and with the composition being free of a polypeptide consisting of amino acids 20 to 111 of SEQ ID NO: 24.

Stated Advantages

Documented Applications