Bifunctional molecules for treatment of immune disorders
Inventors
Tsurushita, Naoya • Tso, J. Yun
Assignees
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Publication Number
US-11993657-B2
Publication Date
2024-05-28
Expiration Date
Abstract
The invention provides bifunctional molecules including an antibody specifically binding to CD122 and an extracellular domain of CTLA-4. The bifunctional molecules specifically bind to CD122 and CTLA-4 ligands, CD80 and CD86 and inhibit their function in immune activation. The bifunctional molecules can inhibit interaction of CD122 with its ligands IL-2 and IL-15 and inhibit interaction of CD80 and CD86 with their counter-receptor, CD28. These bifunctional molecules can suppress Signals 2 and 3 of immune responses as a single therapeutic agent for treatment of immune disorders.
Core Innovation
The invention relates to a bifunctional molecule comprising an antibody that binds to CD122 and inhibits its interaction with IL-2 and IL-15, and a CTLA-4 extracellular domain linked to the antibody. The CTLA-4 extracellular domain blocks the CD80/CD86 interaction with CD28, thereby suppressing Signals 2/3, while the CD122-binding antibody inhibits CD122 interactions with IL-2 and IL-15, thereby blocking Signal 3.
The bifunctional molecule is constructed using antibody chain architectures in which a mature light chain and a mature heavy chain are linked to the CTLA-4 extracellular domain, including chain configurations where a C-terminal lysine can be omitted. The document describes multiple CTLA-4 extracellular domain sequence identifiers and antibody chain sequence identifiers, including configurations with specific mature heavy chain sequences and specific mature light chain sequences.
The invention further includes defined sequence-identity requirements for the CTLA-4 extracellular domain and specifies the heavy chain and light chain variable region CDRs using SEQ ID NOS. The document also describes Fc effector-reducing mutations, including L234A/L235A, and specific antibody formats such as a human IgG1 kappa isotype.
Claims Coverage
The provided claims include six independent claim families. Each independent claim defines a bifunctional molecule that combines CD122 inhibition with a CTLA-4 extracellular domain, with the inventive features primarily focused on the specified antibody/CTLA-4-linked construct architecture and sequence-defined chain components, including options such as omission of a C-terminal lysine and defined variable-region CDR sequences.
CD122-binding antibody linked to CTLA-4 extracellular domain with SEQ ID-defined chains
A bifunctional molecule comprising an antibody that binds to CD122 and inhibits its interaction with IL-2 and IL-15, wherein the mature light chain is linked to a CTLA-4 extracellular domain as a chain comprising SEQ ID NO:34 or 42 and a mature heavy chain comprising SEQ ID NO:8 or 33 provided the C-terminal lysine can be omitted, or wherein the mature heavy chain is linked to a CTLA-4 extracellular domain as a chain comprising SEQ ID NO:39 provided the C-terminal lysine can be omitted, and the mature light chain comprises SEQ ID NO:9.
SEQ ID-defined heavy chain linked to CTLA-4 extracellular domain paired with SEQ ID-defined light chain
A bifunctional molecule comprising a mature heavy chain linked to a CTLA-4 extracellular domain as a chain comprising SEQ ID NO:13 or 16 and a mature light chain comprising SEQ ID NO:9.
SEQ ID-defined heavy chain linked to CTLA-4 extracellular domain paired with SEQ ID-defined light chain
A bifunctional molecule comprising a mature heavy chain linked to a CTLA-4 extracellular domain as a chain comprising SEQ ID NO:57 and a mature light chain comprising SEQ ID NO:54.
SEQ ID-defined heavy chain linked to CTLA-4 extracellular domain with omission option and SEQ ID-defined light chain
A bifunctional molecule comprising a mature heavy chain linked to a CLTA-4 extracellular domain as a chain comprising SEQ ID NO:56 provided the C-terminal lysine can be omitted, and the mature light chain comprises SEQ ID NO:54.
CD122-binding antibody with specified variable-region CDRs linked to CTLA-4 extracellular domain by identity requirement
A bifunctional molecule comprising an antibody that binds to CD122 and inhibits its interaction with IL-2 and IL-15, wherein the antibody comprises a heavy chain comprising a mature heavy chain variable region linked to a heavy chain constant region, and a light chain comprising a mature light chain variable region linked to a light chain constant region, wherein the antibody is linked to a CTLA-4 extracellular domain having at least 90% sequence identity with SEQ ID NO:10 and the mature heavy chain variable region comprises three heavy chain CDRs comprising SEQ ID NOS:59-61 respectively and the mature light chain variable region comprises three light chain CDRs comprising SEQ ID NOS:63-65 respectively.
SEQ ID-defined heavy chain linked to CTLA-4 extracellular domain paired with SEQ ID-defined light chain
A bifunctional molecule comprising a mature heavy chain linked to a CTLA-4 extracellular domain as a chain comprising SEQ ID NO:71 and a mature light chain comprising SEQ ID NO:67.
Across the independent claims, the core inventive subject matter is a bifunctional molecule that combines an antibody inhibiting CD122 interactions with IL-2 and IL-15 together with a linked CTLA-4 extracellular domain. The main claim coverage is grounded in specific, SEQ ID-defined antibody chain architectures and sequence-defined variable-region elements, including conditions such as omission of a C-terminal lysine and a CTLA-4 extracellular domain identity requirement.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Autoimmune diseases including vitiligo, alopecia areata, type 1 diabetes, celiac disease, multiple sclerosis, polymyositis, allergic dermatitis, primary biliary cirrhosis, Behçet’s disease, and ulcerative colitis (autoimmune-disease treatment methods).
Skin allograft rejection (treatment by administering the bifunctional molecule of claim 1).
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