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HUMAN IgG Fc DOMAIN VARIANTS WITH IMPROVED EFFECTOR FUNCTION

A technology of variants and effective doses, applied in the field of human IgGFc domain variants

Pending Publication Date: 2020-10-02
THE ROCKEFELLER UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, various challenges remain (Klein et al., 2012, MAbs.4(6):653-663)

Method used

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  • HUMAN IgG Fc DOMAIN VARIANTS WITH IMPROVED EFFECTOR FUNCTION
  • HUMAN IgG Fc DOMAIN VARIANTS WITH IMPROVED EFFECTOR FUNCTION
  • HUMAN IgG Fc DOMAIN VARIANTS WITH IMPROVED EFFECTOR FUNCTION

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0145] This example describes the materials and methods used in Examples 2 to 3 below

[0146] Materials and Methods

[0147] mouse strain

[0148] All mouse in vivo experiments were performed in accordance with federal law and institutional guidelines and were approved by the Institutional Animal Care and Use Committee of Rockefeller University. Mice were bred and maintained at the Comparative Bioscience Center, Rockefeller University. The following strains were used for experiments: (i) FcγR-deficient mice (FcγR 空 ), previously developed and characterized in Smith, P. et al., Pro Natl Acad Sci US A 109, 6181-6186 (2012); (ii) FcγR humanized mouse (mFcγRα 空 , Fcgr1 - / - , hFCGR1A + , hFCGR2A + , hFCGR2B + , hFCGR3A + , hFCGR3B + ), generated and extensively characterized in Smith, P. et al., Pro Natl Acad Sci US A 109, 6181-6186 (2012); (iii) FcγR / FcRn humanized mouse (m FcγRα 空 , Fcgr1 - / - , Fcgrt - / - , hFCGR1A + , hFCGR2A + , hFCGR2B + , hFCGR3A + , hFCGR3B ...

Embodiment 2

[0158] An Fc domain variant (termed GASDALIE) containing specific mutations (G236A / S239D / A330L / I332E) on the amino acid backbone of human IgGl was developed. It exhibits selectively enhanced binding to human activating FcγRs, FcγRIIa and FcγRIIIa (Smith, P., DiLillo, D.J., Bournazos, S., Li, F. & Ravetch, J.V. Mouse model recapitulating human Fcgamma receptor structural and functional diversity. Proc Natl Acad Sci U S A 109, 6181-6186 (2012)). In a variety of antibody-mediated protection models against bacterial and viral infections, the protective activity of the GASDALIE Fc domain variant of the protective mAb was demonstrated to be significantly enhanced compared to wild-type human IgG1. See Smith, P. et al., Pro Natl Acad Sci US A 109, 6181-6186 (2012); Bournazos, S. et al., Cell 158, 1243-1253 (2014); Bournazos, S. et al., J ClinInvest 124, 725- 729 (2014); and DiLillo, D.J. et al., Nat Med 20, 143-151 (2014).

[0159] More importantly, evaluation of the therapeutic act...

Embodiment 3

[0164] To further extend the in vivo half-life of the GAALIE variant, it was combined with mutations that increased FcRn affinity without affecting FcγR binding (Zalevsky, J. et al., Nat Biotechnol 28, 157-159 (2010) and Grevys, A. et al., J Immunol. 194, 5497-5508 (2015)). These mutations included M428L and N434S (LS variants, Zalevsky, J. et al., Nat Biotechnol 28, 157-159 (2010)), and the amino acid sequences of the resulting Fc domain variants are shown in Figure 16 middle. Determination of protein melting temperature and binding affinity of FcγR / FcR-enhanced variants to FcRn ( Figure 17-20 ). Furthermore, the in vivo half-lives of these variants were evaluated in FcRn / FcγR humanized mice ( FIG. 21 ). As expected, GAALIE LS (G236A / A330L / I332E / M428L / N434S) showed prolonged half-life, which also translated into prolonged and enhanced Fc effects in the mAb-mediated platelet clearance model in FcγR / FcRn humanized mice child activity ( Figure 22 ).

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Abstract

The present invention relates to human IgG Fc domain variants with improved effector function and uses thereof.

Description

[0001] Cross References to Related Applications [0002] This patent document claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application 62 / 607,591, filed December 19, 2017. The aforementioned patent applications are hereby incorporated by reference in their entireties to provide a continuing disclosure. [0003] government interest [0004] This invention was made with government support under P01 AI100148 awarded by NIAID and NIH. The Government has certain rights in this invention. [0005] field of invention [0006] The present invention relates to human IgG Fc domain variants with improved effector functions and uses thereof. [0007] Background of the invention [0008] Extensive experience from the clinical use of many FDA-approved monoclonal antibodies (mAbs) for the treatment of inflammatory and neoplastic conditions strongly suggests that the therapeutic potential of an antibody is highly dependent on the IgG Fc domain and its cognate receptor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/18C07K16/28G01N33/53A61K39/395
CPCC07K16/18C07K16/30C07K16/2887C07K16/462A61P29/00A61P35/00A61P31/00C07K2317/52C07K2317/94C07K2317/24C07K2317/21C07K2317/92C07K2319/33A61K2039/505C07K16/00C07K2317/732C07K2317/734C12N15/85C12N2015/8518C07K2319/035C07K2319/35G01N33/563
Inventor 杰夫瑞·V·华弗治S·布尔纳佐斯
Owner THE ROCKEFELLER UNIV
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