Method of manufacturing bispecific antibodies, bispecific antibodies and therapeutic use of such antibodies

Abstract

The invention relates to bivalent bispecific monoclonal antibodies (bbmAb) or variants thereof, and methods of manufacturing such antibodies by co-expressing modified Fc-mutated derivatives of two different monoclonal antibodies in mammalian cell lines.

Description

STATEMENT OF RELATED APPLICATIONS[0001]This application claims priority to U.S. provisional patent application No. 62 / 518,090, filed Jun. 12, 2017, the contents of which are incorporated herein by reference in their entirety.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on May 30, 2018, is named PAT057716-WO-PCT_SL.txt and is 68,498 bytes in size.TECHNICAL FIELD[0003]The invention relates to bivalent bispecific monoclonal antibodies (bbmAb) or variants thereof, and methods of manufacturing such antibodies by co-expressing so called knob-into-hole modified FC-mutated derivatives of two different monoclonal antibodies in mammalian cell lines.BACKGROUND OF THE DISCLOSURE[0004]Bispecific antibodies, i.e. antibodies binding to two distinct epitopes, are well known in the art. One approach for generating bispecific antibodies...

AI Technical Summary

Benefits of technology

[0010]There is a need to provide an improved method for manufacturing of bivalent bispecific antibodies. Particularly, there is a need for a method for manufacturing of bivalent bispecific monoclonal antibodies (bbmAb), ensuring a sufficient overall yield, purity and product quality to proceed with clinical development and commercial manufacturing, at a reasonable cost.

[0011]The present invention provides inter alia a method for the generation of bbmAbs with one or more of the following advantages: it enables the use of a large antibody repertoire to identify binders as no shared light or heavy chains are required, it does not require any extensive protein engineering, beside the mutation driving the H-chain dimerization, and therefore limits the risk for anti-drug antibodies, it is cost effective as expression is done in a common cell line, therefore the bbmAb can be produced in one cell culture process without the need for a specific in vitro shuffling and it produces high quality material suitable for human use as product related impurities can be efficiently removed.

[0012]The present invention is useful for identifying antibodies of kappa and lambda type, where the light chains do not show a strong promiscuous binding towards the heavy chain of the counterpart. This makes the antibodies suitable for use in methods of the invention. An advantage of the method may be that antibody combinations where both light chains exchange the original heavy chain binding partner, which results in a product related impurity of the H1L2-H2L1 type, can be deselected. This is advantageous, because such product related impurities are not easy to deplete using state of the art purification processes.

[0013]As will be shown below, embodiments of the invention enable manufacturing of bbmAb by the use of a CHO co-expression at a yield and quality suitable for clinical development and commercialization of biologics.

Problems solved by technology

This is advantageous, because such product related impurities are not easy to deplete using state of the art purification processes.

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