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Biparatopic and multiparatopic antibodies with common light chain and method of use

A paratope, light chain technology, applied in the field of diagnosis and treatment of human diseases, can solve the problem of not being able to maintain the binding affinity of two paratopes at the same time

Active Publication Date: 2019-06-21
XUANZHU BIOPHARMACEUTICAL CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this case, the binding affinity of both paratopes cannot be maintained simultaneously

Method used

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  • Biparatopic and multiparatopic antibodies with common light chain and method of use
  • Biparatopic and multiparatopic antibodies with common light chain and method of use
  • Biparatopic and multiparatopic antibodies with common light chain and method of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0150] Example 1. Binding Potency of Antibodies Comprising Pertuzumab or Trastuzumab Heavy and Common Light Chains.

[0151] The binding potency of the antibody to the antigen HER2 was determined using an ELISA assay. The HER2 extracellular domain was coated on a 96-well plate overnight by adding 0.2ug / 100ul / well of the HER2 extracellular domain solution. Plates were washed 6 times with PBS, blocked with 3% BSA, and incubated for 2 hours. Plates were again washed 6 times with PBS. Anti-HER2 antibody was then added to each well at various concentrations indicated in the figure. After 1 hour of binding, the plate was washed 6 times with PBS. Horseradish peroxidase (HRP)-conjugated secondary antibodies were added and incubated for 1 hr. Add HRP substrate TMB to each well and read luminescence on a plate reader. The data were then fitted to a 4 parameter sigmoid curve to generate IC50s. Each sample was performed in triplicate.

[0152] Figure 8A Results are shown for va...

Embodiment 2

[0153] Example 2. Antibodies comprising modified Pertuzumab or Trastuzumab heavy chains and corresponding wild-type light chains Body binding effect.

[0154] The binding potency of mAbs formed by pairing the modified heavy chain with its wild-type light chain was determined using the same ELISA assay described above (see Table 4). mAbs formed with all three modified Pertuzumab heavy chains showed improved performance compared to Pertuzumab (mAb T1 ) (Fig. 9A). Compared with trastuzumab (mAb T22), mAbs formed with all modified trastuzumab heavy chains showed broadly similar performance, with four out of six showing moderate improvements. (FIG. 9B).

Embodiment 3

[0155] Example 3. Comprising Antibodies of Modified Pertuzumab or Trastuzumab Heavy Chains and Various Common Light Chains Combine potency.

[0156] The binding potency of mAbs formed by pairing the modified heavy chain with various common light chains was determined using the same ELISA assay described above (see Table 5). For mAbs using a modified Pertuzumab heavy chain, the best performer in this experiment was the inclusion of both the T30A and G56A substitutions in the heavy chain, which were comparable to the inclusion of N30S, mAb T43 paired with a common light chain replaced by S56Y and T94W. This light chain performed well in other pairings (consider T44 and T45; Figure 10). Performance was about the same for mAbs using the modified Trastuzumab heavy chain with N54T and D98T substitutions. mAb T47, which lacked the S56Y substitution in the common light chain, performed the worst, while mAb T46, which contained the N30S, S56Y and T94W substitutions in the common ...

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Abstract

The present invention relates to bispecific or multi-specific antibody molecules with two or more paratopes. At least one paratope is Fv or scFv, while the other paratope is in a mono-valent or bivalent Fab. These novel molecules also have an Fc moiety that allows extended half-life in vivo.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 483,456, filed April 9, 2017, the entire contents of which are incorporated herein by reference for all purposes. technical field [0003] The present invention relates to biparatopic and multiparatopic antibody constructs, wherein each antibody construct comprises two or more different paratopes. Different paratopes interact with different epitopes from the same antigen or from two different antigens. These biparatopic antibodies comprise at least two distinct heavy chain variable domains, each paired with a common light chain variable domain. Methods of making these are provided. Also disclosed is its use for the diagnosis and treatment of human diseases. Background technique [0004] Human epidermal growth factor receptor 2 (HER2, also known as ErbB2) is a member of the tyrosine protein kinase receptor ErbB family. It is a type I memb...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P35/00C07K14/71C07K16/28C07K16/30C07K16/32C07K16/46
CPCC07K16/32C07K16/2863A61K47/6801A61P35/00C07K2317/732C07K2317/31C07K2317/92C07K2317/565C07K2317/73A61K2039/505A61K2039/545C07K2317/24C07K2317/526C07K2317/55C07K2317/76C07K2317/515
Inventor 肖守华朱晓东
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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