Integrin antagonists with enhanced antibody dependent cell-mediated cytoxicity activity

Abstract

The present invention relates to novel Fc variants of antibodies that immunospecifically binds to Integrin αvβ3. The Fc variants comprise a variable region that immunospecifically binds to Integrin αvβ3 and a Fc region that further comprises at least one novel amino acid residue which may provide for enhanced effector function. More specifically, this invention provides Fc variants that have modified binding affinity to one or more FcγR and / or C1q. Additionally, the Fc variants have altered antibody dependent cell-mediated cytotoxicity (ADCC) and / or complement dependent cytotoxicity (CDC) activity. The invention further provides methods and protocols for the application of said Fc variants of an antibody that immunospecifically binds to Integrin αvβ3, particularly for therapeutic purposes.

Description

1. CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit under 35 U.S.C. §119(e) of the following U.S. Provisional Application Nos. 60 / 601,634, filed, Aug. 16, 2004 and 60 / 608,852, filed, Sep. 13, 2004. The priority applications are hereby incorporated by reference herein in their entirety for all purposes.2. FIELD OF THE INVENTION [0002] The present invention provides novel antibodies comprising immunologically active fragments of immunoglobulin molecules and an Fc region that further comprises at least one novel amino acid residue of the invention. The present invention also relates to novel antibodies comprising a variable region, or fragment thereof, that immunospecifically binds to Integrin αvβ3 and a Fc region that further comprises at least one high effector function amino acid residue (e.g., 239D, 330L, 332E). The present invention further relates to novel variants of antibodies that immunospecifically bind to Integrin αvβ3 (e.g., VITAXIN® (Wu et...

AI Technical Summary

Benefits of technology

[0026] The present invention additionally provides Fc variants that have altered binding affinity to the complement protein C1q relative to a comparable molecule (e.g., an antibody having an original unmodified Fc region). In one embodiment, the Fc variants have enhanced binding affinity to C1q and enhanced ability to mediate CDC (referred to herein as “CDC activity”). In another embodiment, the Fc variants have reduced binding affinity to C1q and reduced CDC activity relative to a comparable molecule (e.g., an antibody having an original unmodified Fc region). In still another embodiment, the Fc variants of the invention are variants of an antibody that immunospecifically binds to Integrin αvβ3.

[0034] It is a further object of the present invention to provide Fc variants that have enhanced ADCC and / or CDC activity. In one embodiment, Fc variants of the invention have ADCC and / or CDC activity that is at least 2 fold greater then that of a comparable molecule (e.g., an antibody prior to Fc modification). In another embodiment, the Fc variants of the invention have ADCC and / or CDC activity that is between about 2 fold and about 100 fold greater then that of a comparable molecule. In yet another embodiment, the Fc variants of the invention have ADCC and / or CDC activity that is between 2 fold and 100 fold greater then that of a comparable molecule.

[0040] The Fc variants of the present invention may be combined with other Fc modifications (e.g., other amino acid substitutions, altered glycosylation, etc.), including but not limited to modifications that alter Fc ligand binding and / or effector function. The invention encompasses combining an Fc variant of the invention with other Fc modifications to provide additive, synergistic, or novel properties in antibodies or Fc fusions. In one embodiment, the other Fc modifications enhance the phenotype of the Fc variants of the present invention (e.g., Fc variant comprising at least one high effector function amino acid) with which they are combined. For example, if an Fc variant (i.e., incorporating a hinge modification of the invention) is combined with a mutant known to bind FcγRIIIA with a higher affinity than a comparable molecule comprising a wild type Fc region; the combination results in a greater fold enhancement in FcγRIIIA affinity.

[0049] The invention further encompasses treatment protocols that enhance the prophylactic or therapeutic effect of Fc variants with altered binding affinity to one or more Fc ligand (e.g., FcγRs, C1q) and altered ADCC and / or CDC activity that immunospecifically bind to Integrin αvβ3.

Problems solved by technology

Cancerous cells destroy the part of the body in which they originate and then spread to other part(s) of the body where they start new growth and cause more destruction.

Current treatment options, such as surgery, chemotherapy and radiation treatment, are oftentimes either ineffective or present serious side effects.

Different integrins play different roles in each of these biological processes and the inappropriate regulation of their function or activity can lead to various pathological conditions.

All of these approaches pose significant drawbacks for the patient.

Surgery, for example, may be contraindicated due to the health of the patient or may be unacceptable to the patient.

Additionally, surgery may not completely remove the neoplastic tissue.

Radiation therapy is only effective when the neoplastic tissue exhibits a higher sensitivity to radiation than normal tissue, and radiation therapy can also often elicit serious side effects.

As such chemotherapy agents are inherently nonspecific.

In addition almost all chemotherapeutic agents are toxic, and chemotherapy causes significant, and often dangerous, side effects, including severe nausea, bone marrow depression, immunosuppression, etc.

Biological therapies / immunotherapies are limited in number and although more specific then chemotherapeutic agents many still target both health and cancerous cells.

In addition, such therapies may produce side effects such as rashes or swellings, flu-like symptoms, including fever, chills and fatigue, digestive tract problems or allergic reactions.

However, despite widespread use, antibodies are not optimized for clinic use and many have suboptimal anticancer potency.

However, most of the methods disclosed resulted in only modest improvements in FcRγIIIA binding and ADCC activity.

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