Epitope of optimized humanized monoclonal antibodies against activated protein C and uses thereof
Inventors
Zhao, Xiao-Yan • Wilmen, Andreas • Freiberg, Christoph • Linden, Lars • Kim, Ji-Yun • YEGNESWARAN, Subramanian • REGNSTROM, Karin • Egner, Ursula • Wang, Xinquan
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Assignees
Member
Oklahoma Medical Research FoundationFounded in 1946, this independent nonprofit biomedical research institute conducts basic, translational, and clinical research in critical areas such as heart disease, cancer, autoimmune, and neurodegenerative diseases. Its mission focuses on understanding biological mechanisms and advancing diagnostics and therapeutics. Activities include conducting clinical trials, managing a patent portfolio, commercializing biotechnologies, and supporting the biotech community. Research efforts are funded by grants and philanthropy, and the institute hosts advanced facilities, interdisciplinary research teams, and collaborations with academia and industry.
Founded in 1946, this independent nonprofit biomedical research institute conducts basic, translational, and clinical research in critical areas such as heart disease, cancer, autoimmune, and neurodegenerative diseases. Its mission focuses on understanding biological mechanisms and advancing diagnostics and therapeutics. Activities include conducting clinical trials, managing a patent portfolio, commercializing biotechnologies, and supporting the biotech community. Research efforts are funded by grants and philanthropy, and the institute hosts advanced facilities, interdisciplinary research teams, and collaborations with academia and industry.
Publication Number
US-11077187-B2
Publication Date
2021-08-03
Expiration Date
Abstract
Provided are optimized humanized antibodies that selectively bind to and inhibit activated protein C without binding to or inhibiting unactivated protein C. In particular, the antibodies bind to particular epitopes outside the catalytic triad of the active site of human activated protein C. Methods of treatment employing these antibodies are described herein.
Core Innovation
The invention provides optimized humanized monoclonal antibodies that selectively bind activated human protein C but not unactivated protein C, wherein binding localizes to an epitope outside the catalytic triad and largely to the autolysis loop. Lead humanized 1573 derivatives (TPP-3656/3657/3658/3639) and an N85D-modified TPP-4885/BAY1896502 series are generated by germlining and framework-shuffling to reduce immunogenicity and improve expression and thermostability while retaining aPC affinity (VH SEQ ID NO:15; VL SEQ ID NO:19).
The patent addresses the problem of aPC-mediated anticoagulation that impairs coagulation in conditions such as hemophilia, acute or traumatic bleeding and trauma-induced coagulopathy, and that can limit therapeutic options. The disclosed antibodies inhibit aPC anticoagulant activity to protect FVa and FVIIIa from APC-mediated inactivation and to restore thrombin generation and aPTT, while partially affecting amidolytic activity and preserving or enhancing aPC cytoprotective effects.
Claims Coverage
Overview: Two independent claims are present covering a composition claim for a human or humanized monoclonal antibody or antibody fragment and a method claim for treating a subject in need of coagulation by administering such an antibody. Six main inventive features are identified.
Specifically binds activated human protein C but not unactivated human protein C
A human or humanized monoclonal antibody or antibody fragment that is capable of specifically binding activated human protein C, but not unactivated human protein C.
Variable light chain comprising SEQ ID NO:19 with N→D substitution at position 85
An antibody or antibody fragment comprising a variable light chain of SEQ ID NO:19 bearing an N→D substitution at position 85.
Variable heavy chain comprising SEQ ID NO:15
An antibody or antibody fragment comprising a variable heavy chain of SEQ ID NO:15.
Method of treating a subject in need of coagulation by administering the antibody
A method of treating a subject in need of coagulation comprising administering to said subject a human or humanized antibody or human or humanized antibody fragment that specifically binds activated human protein C but not unactivated human protein C.
Antibody for administration comprising variable light chain SEQ ID NO:19 with N→D at position 85
The antibody used in the method comprises a variable light chain of SEQ ID NO:19 bearing an N→D substitution at position 85.
Antibody for administration comprising variable heavy chain SEQ ID NO:15
The antibody used in the method comprises a variable heavy chain of SEQ ID NO:15.
The independent claims cover (1) a human or humanized monoclonal antibody or antibody fragment that specifically binds activated human protein C but not unactivated protein C and is defined by specified variable heavy and light chain sequences including an N→D substitution at light-chain position 85, and (2) a method of treating a subject in need of coagulation by administering that antibody.
Stated Advantages
Selective binding to activated protein C but not unactivated protein C.
Inhibition of aPC anticoagulant activity leading to protection of FVa and FVIIIa from APC-mediated inactivation and restoration of thrombin generation and aPTT.
Preservation or enhancement of aPC cytoprotective effects while blocking anticoagulant activity.
Reduced immunogenicity and improved expression and thermostability achieved by germlining and framework-shuffling.
Acceleration of histone H3/H4 cleavage as a reported functional effect.
Documented Applications
Methods of treating coagulation disorders, including hemophilia.
Treatment of acute bleeding and bleeding associated with traumatic coagulopathy (endogenous acute coagulopathy, EAC) and trauma-induced bleeding.
Use as an adjunct in sepsis.
Inclusion in pharmaceutical compositions comprising the antibody together with a pharmaceutically acceptable carrier or diluent.
Diagnostic and kit uses.
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