Bi-specific monovalent Fc diabodies that are capable of binding CD32B and CD79b and uses thereof
Inventors
Johnson, Leslie S. • Huang, Ling • Shah, Kalpana • Bonvini, Ezio • Moore, Paul A. • Chen, Wei
Assignees
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Publication Number
US-11384149-B2
Publication Date
2022-07-12
Expiration Date
Abstract
The present invention is directed to bi-specific monovalent diabodies that comprise an immunoglobulin Fc Domain (“bi-specific monovalent Fc diabodies”) and are composed of three polypeptide chains and which possess at least one binding site specific for an epitope of CD32B and one binding site specific for an epitope of CD79b (i.e., a “CD32B×CD79b bi-specific monovalent Fc diabody”). The bi-specific monovalent Fc diabodies of the present invention are capable of simultaneous binding to CD32B and CD79b. The invention is directed to such compositions, to pharmaceutical compositions that contain such bi-specific monovalent Fc diabodies and to methods for their use in the treatment of inflammatory diseases or conditions, and in particular, systemic lupus erythematosus (SLE) and graft vs. host disease.
Core Innovation
The invention describes a bi-specific monovalent Fc diabody for treating a B-cell mediated disease or condition, wherein the bi-specific monovalent Fc diabody specifically binds an epitope of CD32B and an epitope of CD79b and possesses an IgG Fc Domain. The diabody comprises a first polypeptide chain, a second polypeptide chain and a third polypeptide chain, with covalent bonding between the chains.
The core structure is defined by a three-chain architecture that uses specific IgG Fc sub-domain composition and Fc CH2 and CH3 domains. The polypeptide chains include a cysteine-containing peptide sub-Domain and polypeptide portions of an IgG Fc Domain with CH2 and CH3 domains, with defined peptide linker separation between sub-domains and an E-coil Domain or a K-coil Domain placed on different polypeptide chains.
The invention further defines a covalently linked monovalent Fc diabody construction in which the first and second polypeptide chains are covalently bonded to one another and the first and third polypeptide chains are covalently bonded to one another, including by disulfide bonds. Antigen-binding domain functionality is specified such that the VL Domain of the first polypeptide chain and the VH Domain of the second polypeptide chain form an antigen-binding domain capable of specific binding to CD32B, while the VH Domain of the first polypeptide chain and the VL Domain of the second polypeptide chain form an antigen-binding domain capable of specific binding to CD79b.
Claims Coverage
The provided set includes two independent claims, each directed to a method of treating a B-cell mediated disease or condition using an administered bi-specific monovalent Fc diabody that binds CD32B and CD79b and contains an IgG Fc Domain. Across the two independent claims, the inventive coverage focuses on the three polypeptide chain, covalent/disulfide connected diabody architecture and the detailed arrangement of Fc sub-domains, coil/linker/spacer components, and antigen-binding domain domain pairing for CD32B and CD79b.
Treating B-cell mediated disease or condition with CD32B×CD79b bi-specific monovalent Fc diabody
Administering an effective amount of a bi-specific monovalent Fc diabody to a subject in need thereof, wherein the bi-specific monovalent Fc diabody specifically binds an epitope of CD32B and an epitope of CD79b and possesses an IgG Fc Domain.
Three covalently linked polypeptide chains forming IgG Fc Domain and antigen-binding domains
The bi-specific monovalent Fc diabody comprises a first polypeptide chain, a second polypeptide chain and a third polypeptide chain, wherein first and second polypeptide chains are covalently bonded to one another and first and third polypeptide chains are covalently bonded to one another, and wherein polypeptide portions of the IgG Fc Domains of the first and third polypeptide chain form the IgG Fc Domain, the VL Domain of the first polypeptide chain and the VH Domain of the second polypeptide chain form an antigen-binding domain capable of specific binding to CD32B, and the VH Domain of the first polypeptide chain and the VL Domain of the second polypeptide chain form an antigen-binding domain capable of specific binding to CD79b.
Specified domain layout with IgG CH2/CH3 sub-domain sequences and coil/linker/spacer architecture
Defining the first polypeptide chain with a cysteine-containing peptide and a polypeptide portion of an IgG Fc Domain having CH2 and CH3 domains, Domain 2 comprising VL of a monoclonal antibody capable of binding CD32B and VH of a monoclonal antibody capable of binding CD79b separated by peptide linker, Domain 3 comprising an E-coil Domain or a K-coil Domain separated from Domain 2 by peptide linker, and a C-terminal spacer peptide, with the second polypeptide chain including VL(CD79b) and VH(CD32B) separated by Linker 2 and a K-coil or E-coil domain separated from Domain 1 by the peptide linker.
Three-chain sequence/disulfide bonding architecture defined by SEQ ID NO:15, SEQ ID NO:16, and SEQ ID NO:17
The bi-specific monovalent Fc diabody comprises a first polypeptide chain comprising SEQ ID NO:15, a second polypeptide chain comprising SEQ ID NO:16, and a third polypeptide chain comprising SEQ ID NO:17, wherein the first and second polypeptide chains are covalently bonded to one another by a first disulfide bond and the first and third polypeptide chains are covalently bonded to one another by a second disulfide bond.
Overall, the independent claim coverage is directed to administering an effective amount of a CD32B×CD79b bi-specific monovalent Fc diabody with an IgG Fc Domain, built from three covalently linked polypeptide chains. The inventive features are concentrated in the defined three-chain architecture, the pairing of VL/VH domains for CD32B and CD79b, and the Fc CH2/CH3 sub-domain and coil/linker/spacer arrangements, including alternative coil assignments and a disulfide bonding configuration.
Stated Advantages
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