Cytotoxic immunoglobulin
Inventors
Himmler, Gottfried • Mudde, Geert • Bauer, Anton • Redl, Gerda • Woisetschlager, Maximillian
Assignees
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Publication Number
US-10125197-B2
Publication Date
2018-11-13
Expiration Date
Abstract
The invention relates to a cytotoxic modular antibody with a molecular weight of up to 60 kD, specifically binding to a cell surface target with a binding affinity of Kd<10−8 M, a method of producing such antibody and its use as a therapeutic.
Core Innovation
The document discloses cytotoxic modular antibodies that bind specifically to human Her2, including proteins that comprise two polypeptides. Each polypeptide comprises a human IgG1 heavy chain fragment with a CH2 domain and a CH3 domain, and within the CH3 domain the AB loop comprises SEQ ID NO: 191, the CD loop comprises SEQ ID NO: 241, and the EF loop comprises SEQ ID NO: 370.
The disclosed approach treats a subject having cancer expressing human HER2 by administering the Her2-binding protein, including compositions comprising the protein and a pharmaceutically acceptable carrier. The proteins are characterized as cytotoxic, having a binding affinity of Kd < 10^-8 M, and having a molecular weight of up to 60 kD, with the two polypeptides connected via one or more disulfide bonds.
The document also reports antibody loop engineering and selection using yeast display clones and affinity maturation. Her2-binding yeast clones are described with amino-acid substitutions in antibody structural loops after pool expansion and affinity maturation, and selected Fcabs are characterized for binding and effector-related function, including FcRn/Protein A/CD64 comparability to wild-type Fc, antigen binding to Her2, and ADCC-mediated SKBR3 apoptosis.
Claims Coverage
The provided material includes three independent claims. Across these claims, the main inventive features are directed to treating cancer expressing human HER2 using a specifically defined two-polypeptide human IgG1 heavy chain fragment protein with CH3 loop sequences set by SEQ ID NO: 191, SEQ ID NO: 241, and SEQ ID NO: 370, with additional constraints including cytotoxicity, binding affinity, molecular weight, and pharmaceutical composition with a pharmaceutically acceptable carrier.
Her2-specific two-polypeptide IgG1 heavy chain fragment with defined CH3 loops
Treating a subject having cancer expressing human HER2 by administering a protein that binds specifically to human Her2, where the protein comprises two polypeptides and each polypeptide comprises a human IgG1 heavy chain fragment comprising a CH2 domain and a CH3 domain, wherein the CH3 domain comprises an AB loop comprising SEQ ID NO: 191, a CD loop comprising SEQ ID NO: 241 and an EF loop comprising SEQ ID NO: 370.
Cytotoxic Her2-binding protein meeting molecular weight and Kd constraints
Treating a subject having cancer expressing human HER2 by administering a protein that specifically binds to human Her2, where the protein comprises two polypeptides each comprising a human IgG1 heavy chain fragment with CH2 and CH3 domains and CH3 loop sequences of SEQ ID NO: 191, SEQ ID NO: 241 and SEQ ID NO: 370, wherein the protein has a molecular weight of up to 60 kD, a binding affinity of Kd <10^-8 M and is cytotoxic.
Pharmaceutical composition with Her2-specific two-polypeptide IgG1 heavy chain fragment
Treating a subject having cancer by administering a pharmaceutical composition comprising a protein that binds specifically to human Her2 and a pharmaceutically acceptable carrier, where the cancer expresses human HER2 and the protein comprises two polypeptides, each comprising a human IgG1 heavy chain fragment with CH2 and CH3 domains, and wherein the CH3 domain comprises an AB loop comprising SEQ ID NO: 191, a CD loop comprising SEQ ID NO: 241 and an EF loop comprising SEQ ID NO: 370.
The independent claim set centers on methods of treating cancer expressing human HER2 using a specifically defined, two-polypeptide human IgG1 heavy chain fragment protein with CH3 AB/CD/EF loop sequences of SEQ ID NO: 191, SEQ ID NO: 241, and SEQ ID NO: 370, optionally further constrained to be cytotoxic and meet Kd and molecular weight limits. One independent claim further frames the treatment as a pharmaceutical composition including the protein and a pharmaceutically acceptable carrier.
Stated Advantages
Cytotoxic activity against cancer expressing human HER2.
Higher binding affinity, with a binding affinity of Kd <10^-8 M in the independent claim recited set.
Fc-related binding comparability to wild-type Fc, including FcRn/Protein A/CD64 binding comparability.
Demonstrated ADCC-mediated SKBR3 apoptosis with reported EC50 values for lead Fcabs.
Documented Applications
Treating a subject having cancer expressing human HER2 by administering a Her2-binding protein with defined IgG1 heavy chain fragment CH3 loop sequences.
Use of a pharmaceutical composition comprising the Her2-binding protein and a pharmaceutically acceptable carrier for treating cancer expressing human HER2.
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