High affinity humanized anit-cea monoclonal antibodies

Abstract

Novel humanized monoclonal antibodies, fragments or derivatives thereof which specifically bind carcinoembryonic antigen (CEA) are provided as well as methods for their manufacture. These humanized antibodies are useful in the treatment of cancers which express CEA as well as for diagnostic purposes, e.g., for in vivo imaging of tumors or cancer cells which express CEA.

Description

[0001] The present invention relates to humanized monoclonal antibodies and fragments or derivatives thereof which specifically bind carcinoembryonic antigen (CEA), which is an antigen expressed by various human carcinomas including breast, lung, and gastrointestinal carcinomas such as stomach and colon cancers. More specifically, the present invention relates to humanized monoclonal antibodies and humanized antibody fragments and derivatives thereof which are derived from murine monoclonal antibody COL-1, a high affinity anti-CEA antibody. The present invention further relates to methods for producing such humanized monoclonal antibodies specific to CEA, pharmaceutical and diagnostic compositions containing such humanized monoclonal antibodies, and methods of use thereof for the treatment or diagnosis of cancer.[0002] The identification of antigens expressed by tumor cells and the preparation of monoclonal antibodies which specifically bind such antigens is well known in the art. A...

AI Technical Summary

Benefits of technology

The humanized antibodies exhibit reduced immunogenicity, improved plasma clearance, and retained antigen-binding affinity, enabling repeated administration without significant adverse responses, making them suitable for prolonged cancer treatment and diagnosis.

Problems solved by technology

However, while murine antibodies, such as COL-1 and other anti-CEA murine antibodies, have applicability as therapeutic agents in humans, they are disadvantageous in some respects.

This may result in a neutralizing antibody response--a human anti-murine antibody (HAMA) response--which is particularly problematic if the antibodies are desired to be administered repeatedly, e.g., for treatment of a chronic or recurrent disease condition.

This is a significant drawback, as some cancer treatments are effected over a prolonged time period, e.g., over several years or longer.

However, while such chimerized monoclonal antibodies typically exhibit lesser immunogenicity, they are still potentially immunogenic in humans because they contain murine variable sequences which may elicit antibody responses.

Thus, there is the possibility that these chimeric antibodies may elicit an anti-idiotypic response if administered to patients.

However, CDR-grafting by itself may not yield the desired result.

Given these effects of changes in amino acid residues, although humanized antibodies are desirable because of their potential low immunogenicity in humans, their production is unpredictable.

For example, sequence modification of antibodies may result in substantial or even total loss of antigen binding affinity, or loss of binding specificity.

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