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Bispecific antibodies against cd3 and cd20

a technology applied in the field of cd3 and cd20, can solve the problems of low efficacy and disappointing initial clinical studies, and achieve the effects of rapid and strong cell killing, high killing efficiency, and high potency in eradicating tumor cells

Pending Publication Date: 2020-06-25
GENMAB AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0019]The novel CD3xCD20 bispecific antibodies are useful in therapeutic settings in which specific targeting and T cell-mediated killing of cells that express CD20 is desired. The novel CD3xCD20 bispecific antibodies are highly efficient in killing CD20 expressing cells, including cells with low CD20 copy numbers, and have been shown to be highly potent in eradicating tumor cells in animal models. The novel CD3xCD20 bispecific antibodies are advantageous by inducing rapid and strong killing of cells at low dosing. The novel CD3xCD20 bispecific antibodies are furthermore capable of inducing cytotoxicity by both CD4+ T cells and CD8+ T cells which makes them suitable for engaging T cells for killing CD20 positive tumors and other diseases involving CD20 positive cells. In addition, the CD3xCD20 bispecific antibodies are efficient in depleting B cells from lymphoid structures. Accordingly, it is an object of the present invention to provide a bispecific CD3xCD20 antibody which is capable of inducing cytotoxicity by both CD4+ T cells and CD8+ T cells. It is a further object of the present invention to provide a bispecific CD3xCD20 antibody which is highly efficient in killing CD20 expressing cells such as CD20 expressing tumor cells. It is a further object of the present invention to provide a bispecific CD3xCD20 antibody which is highly efficient in killing CD20 expressing cancers.

Problems solved by technology

However, initial clinical studies were rather disappointing mainly due to low efficacy, severe adverse effects (cytokine storm) and immunogenicity of the bispecific antibodies (Muller and Kontermann, 2010, BioDrugs 24: 89-98).

Method used

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  • Bispecific antibodies against cd3 and cd20
  • Bispecific antibodies against cd3 and cd20
  • Bispecific antibodies against cd3 and cd20

Examples

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example 1

n of Humanized CD3 Antibodies and Non-Activating Antibody Variants

Humanization of CD3 Antibodies

[0658]Humanization of a murine CD3 antibody SP34 (U.S. Pat. No. 8,236,308, described herein as IgG1-CD3) was performed by Antitope (Cambridge, UK) using their improved version of the germline humanization (CDR-grafting) technology (EP0629240). Using this technology, 4 different VH chains (SEQ ID NOs:6, 7, 8, and 9) and 3 different VL chains (SEQ ID NOs:10, 11, and 12) were designed. By combining these 4 VH with the 3 VL chains, 12 different antibodies were generated. The humanized variants are described herein as huCD3. Thus, humanized variants comprising a VH and a VL according to the invention, are described as, e.g., IgG1-huCD3-H1L1 meaning that said specific variant is of the IgG1 isotype, is a humanized SP34 CD3-specific antibody and comprises the VH amino acid sequence termed “H1” and is defined according to SEQ ID NO:6, and the VL amino acid sequence termed “L1” and is defined acco...

example 2

n of Bispecific Antibodies by 2-MEA-Induced Fab-Arm Exchange

[0681]An in vitro method for producing bispecific antibodies is described in WO2008119353 (Genmab) and reported by van der Neut-Kolfschoten et al. (Science. 2007 Sep. 14; 317(5844):1554-7). Herein, the bispecific antibodies were formed by “Fab-arm” or “half-molecule” exchange (swapping of a heavy chain and attached light chain) between two monospecific IgG4- or IgG4-like antibodies upon incubation under mildly reducing conditions. Without being limited to theory, this Fab-arm exchange reaction was the result of a disulfide-bond isomerization reaction wherein the inter heavy-chain disulfide bonds in the hinge regions of monospecific antibodies were reduced and the resulting free cysteines form a new inter heavy-chain disulfide bond with cysteine residues of another antibody molecule with a different specificity. The resulting products were bispecific antibodies having two Fab arms with different sequences.

[0682]The knowledge...

example 3

n of Mutants to Optimize the Production of the Humanized CD3 Antibodies

[0685]Generation of huCD3-L1 Mutant Plasmids

[0686]Several IgG1-huCD3-H1L1 variants with mutations in the L1 light chain were generated in order to improve the expression levels of IgG1-huCD3-H1L1 in transient transfection assays, cf. Table 5. The selection of residues was based on comparisons with germline sequences or screening for the presence of rare residues in the huCD3-L1 sequence in combination with crystal structures from homologous antibodies. The selected sequences were synthesized at GeneArt (Life Technologies, Germany). p33L encodes the constant domain of the human IgLC2 / IgLC3 lambda light chain of SEQ ID NO:29. p33Glf encodes the IgG1m(f) heavy chain constant region of SEQ ID NO: 15.

TABLE 5Antibody name after co-expressionLC constructsLC Mutantswith HC VH1 encoding plasmidp33L-huCD3-VL1—IgG1-huCD3-H1L1p33L-huCD3-VL1-F10LF10LIgG1-huCD3-H1L1-LF10Lp33L-huCD3-VL1-R23AR23AIgG1-huCD3-H1L1-LR23Ap33L-huCD3-V...

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Abstract

Bispecific antibodies directed to CD3 and CD20 and uses of such bispecific antibodies, in particular use thereof in the treatment of diseases in which specific targeting and T cell-mediated killing of cells that express CD20 is desired.

Description

REFERENCE TO RELATED APPLICATIONS[0001]This application is a divisional of U.S. patent application Ser. No. 15 / 541,594, filed Jul. 5, 2017 (now U.S. Pat. No. 10,544,220), which is a 35 U.S.C. 371 national stage filing of International Application No. PCT / EP2016 / 050296, filed Jan. 8, 2016, which claims priority to International Application No. PCT / EP2015 / 050276, filed Jan. 8, 2015 and Danish Patent Application Nos. PA 2015 00412, filed Jul. 15, 2015; PA 2015 00413, filed Jul. 15, 2015; PA 2015 00415, filed Jul. 16, 2015; and PA 2015 00416, filed Jul. 16, 2015. The contents of the aforementioned applications are hereby incorporated by reference.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 Dec. 4, 2019, is named GMI_147USEDV_Sequence_Listing.txt and is 83,702 bytes in size.FIELD OF THE INVENTION[0003]The present invent...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/28A61K39/395C07K16/30
CPCC07K16/2887A61K2039/505C07K16/2809C07K2317/732C07K2317/21C07K2317/24C07K2317/73C07K2317/90C07K2317/75C07K2317/92A61K39/39558C07K2317/567C07K16/30C07K2317/31C07K2317/94A61P35/00A61P35/02C07K2317/56C07K2317/565C07K2317/52
Inventor ENGELBERTS, PATRICKBREIJ, ESTHERRADEMAKER, RIKALTINTAS, ISILSATIJN, DAVIDVERPLOEGEN, SANDRAVAN DIJKHUIZEN RADERSMA, RIEMKEVAN DEN BRINK, EDWARDSCHUURMAN, JANINEPARREN, PAUL
Owner GENMAB AS
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