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BCMA (CD269/TNFRSF17) binding proteins

A protein-binding and fragment-binding technology, applied in the field of human BCMA (hBCMA) antigen-binding protein and its fragments, can solve problems such as low expression

Active Publication Date: 2014-02-05
GLAXO GRP LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although purified plasma cells from MGUS patients had lower expression of BCMA, there was no significant difference when compared with the expression found in normal plasma cells or myeloma cells

Method used

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  • BCMA (CD269/TNFRSF17) binding proteins
  • BCMA (CD269/TNFRSF17) binding proteins
  • BCMA (CD269/TNFRSF17) binding proteins

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0277] Preparation of ADCs:

[0278] In antibody drug conjugates, the antibody can be conjugated to a cytotoxic agent either directly or via a linker. Suitable linkers include, for example, cleavable and non-cleavable linkers. A cleavable linker is typically readily cleavable under intracellular conditions. Suitable cleavable linkers include, for example, peptide linkers cleavable by intracellular proteases, such as lysosomal or endosomal proteases. In an exemplary embodiment, the linker may be a dipeptide linker, such as a valine-citrulline (val-cit) or phenylalanine-lysine (phe-lys) linker. Other suitable linkers include linkers that are hydrolyzable at pH below 5.5, such as hydrazone linkers. Additional suitable cleavable linkers include disulfide linkers.

[0279] Bristol-Myers Squibb have described specific lysosomal enzyme-cleavable antineoplastic drug conjugates. See, eg, US Patent No. 6,214,345. Seattle Genetics has published applications US Patent Application No...

Embodiment 1

[0302] Example 1 Production and Selection of Monoclonal Antibodies

[0303] 1.1 Immunization strategy

[0304] The anti-human BCMA mAb murine parental CA8 was identified from a hybridoma derived from mice immunized with full-length human BCMA. BALB / c mice were immunized intraperitoneally with 25 μg of recombinant (rBCMA) protein in combination with CFA. Mice were boosted three times at one-month intervals with 25 μg full-length rBCMA protein + 10 μg monophosphoryl lipid A-stabilized emulsion (MPL-SE) (Corixa Corporation, Seattle, WA) and administered intravenously 3 days before fusion 30 μgrBCMA protein was boosted before the fusion. Hybridomas can be generated and cloned using the ClonaCell-HY Hybridoma Cloning Kit (StemCell Technologies, Vancouver, BC) or using conventional methods. In a conventional approach, B cells from the spleen of immunized animals were fused with Sp2 / 0 myeloma cells in the presence of PEG (Sigma-Aldrich, St. Louis, MO). After overnight recovery, c...

Embodiment 2

[0311] 2.1 Cloning of variable region of CA8 hybridoma

[0312] Total RNA was extracted from CA8 hybridoma cells, followed by reverse transcription and polymerase chain reaction (RT-PCR) to generate light chain variable domain cDNA sequences. The forward primer used for RT-PCR was a mixture of degenerate primers specific for the leader sequence of the murine immunoglobulin genes, and the reverse primer was specific for the antibody constant region. Reverse primers specific for IgGl, IgG2a and IgG2b were used in this example since the isotypes were unknown. To design primers, mouse V H and V k DNA Multiple Sequence Alignment of Gene Leader Sequences.

[0313] 2.2 Cloning of chimeric CA8

[0314] DNA expression constructs encoding chimeric antibodies were made de novo by constructing overlapping oligonucleotides including restriction sites for cloning into mammalian expression vectors as well as human signal sequences. Will Hind III and SpeI Restriction sites were intro...

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Abstract

The present invention concerns antigen binding proteins and fragments thereof which specifically bind B Cell Maturation Antigen (BCMA), particularly human BCMA (hBCMA) and which inhibit the binding of BAFF and APRIL to the BCMA receptor. Further disclosed are pharmaceutical compositions, screening and medical treatment methods.

Description

technical field [0001] The present invention relates to antigen binding proteins and fragments thereof which specifically bind B cell maturation antigen (BCMA) and in particular human BCMA (hBCMA). [0002] The invention also relates to methods of treating diseases or disorders using the antigen-binding fragments, pharmaceutical compositions comprising the antigen-binding fragments, and methods of manufacture. Other embodiments of the invention will be apparent from the description below. Background of the invention [0003] BCMA (CD269 or TNFRSF17) is a member of the TNF receptor superfamily. It is an aglycosylated intrinsic membrane receptor for the ligands BAFF and APRIL. Ligands of BCMA can also bind additional receptors: TACI (transmembrane activator and calcium regulator and cyclophilin ligand interactor), which binds APRIL and BAFF, and BAFF-R (BAFF receptor or BR3), It shows a restricted but high affinity for BAFF. Taken together, these receptors and their corres...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28A61K47/48
CPCC07K16/2878A61K47/48561C07K2317/92C07K2317/77C07K2317/732A61K47/48438C07K2317/76C07K2317/72C07K2317/41A61K2039/505C07K2317/24C07K2317/565C07K2317/33C07K2317/567A61K47/6817A61K47/6849A61P29/00A61P35/00A61P35/02A61P37/02A61K47/50C07K16/28
Inventor P.阿尔盖特S.J.克莱格J.L.克雷根P.A.汉布林A.P.刘易斯R.S.帕马P.梅斯T.A.K.沃塔姆
Owner GLAXO GRP LTD
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