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Multivalent antigen-binding FV molecule

A technology of antigen-binding molecules and antigens, applied in the direction of anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, antibody, anti-inflammatory agent, etc., can solve the problem of tandem diabodies lacking the constant domain of immunoglobulin

Active Publication Date: 2014-03-26
AFFIMED GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Tandem diabodies lacking immunoglobulin constant domains

Method used

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  • Multivalent antigen-binding FV molecule
  • Multivalent antigen-binding FV molecule
  • Multivalent antigen-binding FV molecule

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Divide V for use H A-V L B-V H B-V L The arrangement of the domains outside A constructs a functionalized dimeric tandem diabody ( ), using the two domains of the humanized anti-CD19 single-chain antibody and the humanized anti-CD3 single-chain antibody to use the V of the present invention L A-V H B-V L B-V H The arrangement of the domains of A constructs several such dimeric tandem diabodies. At the same time, the humanized anti-CD39 antibody and the humanized anti-CD3 antibody are subjected to an affinity maturation process, and two variants of each antigen binding molecule are used to confirm the results representing the products of different stages of the affinity maturation process.

[0091] Murine monoclonal antibodies HD37 and UCHT against CD19 and CD3, respectively, are the starting materials for obtaining humanized antibodies with relatively high affinity. In each case, first place V in the scFv phagemid vector H Domain and human V L The library is combined to se...

Embodiment 2

[0119] In vitro T cell receptor regulation by human serum albumin (HSA)×CD3TandAb antibody

[0120] In order to determine whether HSA×CD3TandAb antibodies with different domain sequences have different potency in inducing T cell receptor (TCR) / CD3 regulation in T cells in vitro, cultured in vitro in the presence of increased concentrations of bispecific HSA×CD3TandAb antibodies CD3 + Leukemia cells are then analyzed for the remaining TCR. The conditioning test was performed in the presence or absence of HSA to measure the effect of HSA on TandAb activity.

[0121] In short, 1×10 6 A single leukemia cell was inoculated into each well of a round-bottom 96-well microplate in RPMI1640 medium supplemented with 2mM L-glutamine and 100IU / mL penicillin G sodium salt and 100μg / mL sulfate chain Mycin (all components are from Invitrogen). In different microtiter plates, leukemia cells were seeded in the aforementioned RPMI medium, but 50 mg / mL HSA (Sigma) was added to it. After adding the ...

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Abstract

In one aspect, the present invention relates to an antigen-binding molecule specific for albumin and CD3 comprising two polypeptide chains, each polypeptide chain having at least four variable domains in an orientation preventing Fv formation and the two polypeptide chains are dimerized with one another thereby forming a multivalent antigen-binding molecule. On each of the two polypeptide chains the four variable domains are arranged in the order VLA-VHB-VLB-VHA from the N-terminal to the C-terminal of the polypeptide. Compositions of the antigen-binding molecule and the methods of using the antigen-binding molecule or the compositions thereof for treatment of various diseases are also provided herein.

Description

Technical field [0001] The invention relates to a novel tandem Fv diabody and its use. Background technique [0002] Various forms of multivalent recombinant antibody fragments have been designed as alternatives to cell hybridoma-derived antibodies. [0003] US7129330, Kipriyanov et al. J. Mol. Biol. (1999) 293, 41-56 and Kipriyanov Meth. Mol. Biol. (2009) 562, 177-193 describe the construction and production of specific forms of multivalent antibody fragments, due to their The design is based on the variable domain V of two different polypeptides H And V L The intermolecular pairing of diabodies, as described for diabodies (Holliger et al., 1993, Proc. Natl. Acad. Sci. USA, 90: 6444-6448), so it was named "tandem diabodies" (tandem diabodies) ( ). The antibody is bispecific for CD19 and CD3. With divalent scFv-scFv (scFv) 2 In tandem comparison, the tandem diabodies are tetravalent because they have four antigen binding sites. The sequence of domains from the N-terminus to th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/46C07K16/28
CPCC07K2317/24C07K16/468C07K2317/35C07K2317/62C07K2317/73C07K2317/31C07K16/2809C07K16/2803C07K2317/626A61K2039/505C07K2319/00A61P29/00A61P31/04A61P35/00A61P35/02A61P35/04A61P37/06A61P37/08
Inventor 马威廉·利透伐布芮斯·勒盖儿
Owner AFFIMED GMBH
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