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JP-7857273-B2 - Heterodimeric antibodies that bind to CD3 and tumor antigens

JP7857273B2JP 7857273 B2JP7857273 B2JP 7857273B2JP-7857273-B2

Inventors

  • ムーア，グレゴリー
  • デスジャルライス，ジョン
  • バーネット，マシュー
  • シュー，セウン
  • ラシド，ルマーナ
  • ムシャール，ウメシュ
  • リー，スン－ヒュン

Assignees

  • ゼンコー・インコーポレイテッド

Dates

Publication Date
20260512
Application Date
20231208
Priority Date
20141126

Claims (5)

  1. a) A variable heavy chain domain comprising vhCDR1 of SEQ ID NO: 422, vhCDR2 of SEQ ID NO: 423, and vhCDR3 of SEQ ID NO: 424, and b) A variable light chain domain comprising vlCDR1 of SEQ ID NO: 426, vlCDR2 of SEQ ID NO: 427, and vlCDR3 of SEQ ID NO: 428 , wherein the CD20 binding domain of the antibody comprises these domains.
  2. a) a first nucleic acid encoding a variable heavy chain domain as described in claim 1 , and b) a nucleic acid composition comprising a second nucleic acid encoding a variable light chain domain as described in claim 1 .
  3. An expression vector composition comprising the nucleic acid composition described in claim 2 , an expression vector composition comprising a) a first expression vector containing the first nucleic acid, and b) a second expression vector containing the second nucleic acid.
  4. A host cell comprising the expression vector composition described in claim 3 .
  5. A method for producing the CD20 binding domain of an antibody according to claim 1 , comprising culturing the host cell according to claim 4 under conditions in which the CD20 binding domain of the antibody is expressed, and recovering the CD20 binding domain of the antibody .

Description

Cross-reference of related applications This application is a reference to the following applications filed under 35 U.S.C. §119(e): U.S. Provisional Patent Application No. 62/085,117, filed on 26 November 2014; U.S. Provisional Patent Application No. 62/084,908, filed on 26 November 2014; U.S. Provisional Patent Application No. 62/085,027, filed on 26 November 2014; U.S. Provisional Patent Application No. 62/085,106, filed on 26 November 2014; and the application filed on 8 May 2015. We claim priority to U.S. Provisional Patent Application No. 62/159,111, U.S. Provisional Patent Application No. 62/251,005 filed on November 4, 2015, and U.S. Provisional Patent Application No. 62/250,971 filed on November 4, 2015 (all of which, together with certain references therein to the figures, descriptions and claims, are expressly incorporated herein by reference). Antibody-based therapies are used and have been effective in treating a variety of diseases, including cancer and autoimmune/inflammatory disorders. However, improvements are still needed for this class of drugs, particularly in enhancing their clinical efficacy. One approach is to modify antibody-based drugs by adding an additional and novel antigen-binding site so that a single immunoglobulin molecule co-associates with two different antigens. Such unnatural or alternative antibody forms that associate with two different antigens are called bispecific antibody forms. Often referred to as cs, the remarkable diversity of antibody variable regions (Fv) makes it possible to create Fv that substantially recognize any molecule. Therefore, a typical method for creating bispecific antibodies is the introduction of a novel variable region into the antibody. Several alternative antibody formulations targeting bispecificity are being explored (Chames & Baty, 2009, mAbs 1[6]:1-9; Holliger & Hudson, 2005, Nature Biotechnology 23[9]:1126-113 6; Kontermann, mAbs 4(2):182 (2012), all of which are expressly incorporated herein by reference). Initially, bispecific antibodies were created by fusing two cell lines, each producing a single monoclonal antibody (Mi Istein et al., 1983, Nature 305:537-540. Although the resulting hybrid hybridomas or quadromas did indeed produce bispecific antibodies, they were only small populations, and large-scale purification was required to isolate the desired antibodies. An engineering solution to this was the use of antibody fragments to produce bispecific antibodies. Since such fragments lack the complex quaternary structure of full-length antibodies, the variable light chain and variable heavy chain can be linked in a single genetic construct. Many different forms of antibody fragments have been produced, including bispecific antibodies, single-stranded bispecific antibodies, tandem scFv types, and Fab2 bispecific antibodies (Chames & Baty, 2009, mAbs 1[6]:1-9). ; Holliger & Hudson, 2005, Nature Biotechnolo (gy 23[9]:1126–1136; expressly incorporated herein by reference) While these forms can be expressed at high levels in bacteria and their small size may offer desirable permeability advantages, they are rapidly eliminated in vivo, presenting production challenges regarding their production and stability. The main reason for these drawbacks is the lack of a constant region of the antibody with its relevant functional properties, including a larger size, high stability, and binding ability to various Fc receptors and ligands, which would allow the antibody fragment to maintain a long half-life in serum (i.e., neonatal Fc receptor FcRn) or serve as a binding site for purification (i.e., protein A and protein G). More recent studies have attempted to address the shortcomings of fragment-based bispecificity by modifying the double bond to a full-length antibody-like form (Wu et al., 2007, Na). ure Biotechnology 25[11]:1290-1297; U.S. Patent Application No. 12/477,711; Michaelson et al., 2009. ,mAbs 1[2]:128-141;PCT/U.S. Patent Application Publication No. 2008/074 No. 693; Zuo et al. , 2000, Protein Engineer ing 13[5]:361-367; U.S. Patent Application No. 09/865,198; Shen et al. , 2006, J Biol Chem 281[16]:107 06-10714; Lu et al. , 2005, J Biol Chem 280 [ 20]:19665-19672;PCT/U.S. Patent Application Publication No. US2005/0254 Specification No. 72; expressly incorporated herein by reference). These forms are primarily F The presence of a c-region overcomes some of the drawbacks of bispecific antibody fragments. One notable drawback of these forms is that binding to new antigens is always divalent, as a new antigen-binding site is constructed at the top of the homodimer constant chain. For numerous antigens of interest as simultaneous targets in a bispecific form for therapeutic purposes, the desired binding is monovalent rather than bivalent. In many immune receptors, cell activation is achieved by crosslinking of monovalent binding interactions. The mechanism of crosslinking is typically by antibody/antigen immune complexes. Alternatively, i