Optimized Fc variants and methods for their generation

Abstract

The present invention relates to optimized Fc variants, methods for their generation, and antibodies and Fc fusions comprising optimized Fc variants.

Description

[0001] This application claims benefit under 35 U.S.C. §199(e) to U.S. Pat. Nos. 10 / 672280, filed Sep. 26, 2003, 10 / 379392, filed Mar. 3, 2003, 60 / 477,839 filed Jun. 12, 2003; 60 / 467,606, filed May 2, 2003; 60 / 414,433 filed Sep. 27, 2002; and 60 / 442,301 filed Jan. 23, 2003, all of which are expressly incorporated by reference in their entirety.FIELD OF THE INVENTION [0002] The present invention relates to novel optimized Fc variants, engineering methods for their generation, and their application, particularly for therapeutic purposes. BACKGROUND OF THE INVENTION [0003] Antibodies are immunological proteins that bind a specific antigen. In most mammals, including humans and mice, antibodies are constructed from paired heavy and light polypeptide chains. Each chain is made up of individual immunoglobulin (Ig) domains, and thus the generic term immunoglobulin is used for such proteins. Each chain is made up of two distinct regions, referred to as the variable and constant regions. The...

AI Technical Summary

Benefits of technology

[0023] It is a further object of the present invention to provide Fc variants that have been screened computationally. A computationally screened Fc variant is one that is predicted by the computational screening calculations described herein as having a sig

Problems solved by technology

Yet another level of complexity is the existence of a number of FcγR polymorphisms in the human proteome.

Despite such widespread use, antibodies are not optimized for clinical use.

Two significant deficiencies of antibodies are their suboptimal anticancer potency and their demanding production requirements.

Despite this arsenal of anti-tumor weapons, the potency of antibodies as anti-cancer agents is unsatisfactory, particularly given their high cost.

In these cases depletion of target cells is undesirable and can be considered a side effect.

Effector function can also be a problem for radiolabeled antibodies, referred to as radioconjugates, and antibodies conjugated to toxins, referred to as immunotoxins.

Antibodies must be expressed in mammalian cells, and the currently marketed antibodies together with other high-demand biotherapeutics consume essentially all of the available manufacturing capacity.

First, it dramatically raises the cost of goods to the producer, a cost that is passed on to the patient.

Second, it hinders industrial production of approved antibody products, limiting availability of high demand therapeutics to patients.

Finally, because clinical trials require large amounts of a protein that is not yet profitable, the insufficient supply impedes progress of the growing antibody pipeline to market.

This may result in reduced or even lack of effector function because, as discussed above, the carbohydrate structure can significantly impact FcγR and complement binding.

A potentially greater problem with nonhuman glycoforms may be i

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