Antibodies with immune effector activity and that internalize in folate receptor alpha-positive cells
Inventors
Grasso, Luigi • Nicolaides, Nicholas C. • Sass, Philip M.
Assignees
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Publication Number
US-9522195-B2
Publication Date
2016-12-20
Expiration Date
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” folate receptor alpha (FRA)-specific antibodies that bind FRA-positive cells and, upon binding, alternatively induce immune effector activity such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) and internalize. The antibodies are described as monoclonal and/or polyclonal and are used to target FRA-positive tumor cells, including dysplastic cells.
The invention addresses limitations of prior antibodies by employing FRA-specific antibodies with an in-out behavior that supports both immune effector activity and internalization, thereby enabling targeted delivery of pharmacologic and/or toxic payloads to FRA-positive cells. The payloads include conjugates, such as conjugates of the antibody to a carbohydrate and/or a chemotherapeutic agent.
The disclosure further provides antibody formats including chimeric antibodies, humanized antibodies, and fully human antibodies, and describes producing cells, nucleic acids, and antibody production using cells assigned American Type Culture Collection accession number PTA-7552. The document also describes uses of the antibodies for detection and treatment of FRA-positive dysplastic and tumor cells.
Claims Coverage
Two independent method claims are presented for treating folate receptor-alpha-positive ovarian cancer by administering a therapeutically effective amount of a chemotherapeutic agent together with an antibody produced by cells assigned ATCC accession number PTA-7552, wherein the antibody is conjugated to a carbohydrate and/or chemotherapeutic agent. Across the independent claims, the core inventive structure is the combination of FRA-targeting antibody from PTA-7552 and a therapeutic drug conjugate payload, with different chemotherapeutic agents selected for each independent claim.
Doxorubicin with PTA-7552 conjugated antibody for FRA-positive ovarian cancer
Administering a therapeutically effective amount of doxorubicin and a therapeutically effective amount of the antibody produced by cells assigned ATCC accession number PTA-7552, wherein the antibody is conjugated to a carbohydrate and/or chemotherapeutic agent, for treating folate receptor-alpha-positive ovarian cancer in a subject in need of treatment.
Paclitaxel with PTA-7552 conjugated antibody for FRA-positive ovarian cancer
Administering a therapeutically effective amount of paclitaxel and a therapeutically effective amount of the antibody produced by cells assigned ATCC accession number PTA-7552, wherein the antibody is conjugated to a carbohydrate and/or chemotherapeutic agent, for treating folate receptor-alpha-positive ovarian cancer in a subject in need of treatment.
Both independent claims require administering an ATCC PTA-7552-produced FRA-targeting antibody conjugate (carbohydrate and/or chemotherapeutic agent) in combination with a therapeutically effective amount of a selected chemotherapeutic agent (doxorubicin or paclitaxel) to treat folate receptor-alpha-positive ovarian cancer.
Stated Advantages
Enables targeting of FRA-positive tumor cells, including dysplastic cells, using FRA-specific antibodies that bind FRA-positive cells and internalize.
Provides immune effector activity upon binding, including antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
Supports internalization-dependent killing of FRA-expressing cells using an immunotoxin concept (Hum-ZAP/saporin) where killing depends on FRA expression.
Documented Applications
Treatment of folate receptor-alpha-positive ovarian cancer in a subject in need of treatment using combinations of doxorubicin or paclitaxel with the PTA-7552-produced FRA-specific antibody conjugate.
Detection and treatment of FRA-positive dysplastic and tumor cells using the FRA-specific antibodies.
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