Soluble universal ADCC-enhancing synthetic fusion gene and peptide technology and its use thereof
Inventors
Li, Chiang J. • UNNIRAMAN, SHYAM
Assignees
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Publication Number
US-12247062-B2
Publication Date
2025-03-11
Expiration Date
Abstract
Novel synthetic biology-based ADCC technologies are provided that enhance or enable ADCC responses, for example, through a rationally-designed soluble universal ADCC enhancer protein (SUAEP) where a high-affinity CD3-binding domain is fused to a high-affinity Fc-binding domain. The SUAEP technology can be used to prevent or treat cancers, infectious, inflammatory or autoimmune diseases, and other diseases where elimination of diseased cells is desirable.
Core Innovation
The invention describes a soluble universal adapter-like ADCC enhancer (SUAEP) fusion protein that recruits CD3+ T cells to antibody-coated diseased cells by providing an Fc-binding domain and a CD3-binding domain to crosslink CD3 and amplify antibody-dependent cellular cytotoxicity (ADCC). The Fc-binding domain provides high-affinity binding to an antibody’s Fc fragment, and the disclosure positions the fusion protein as an off-the-shelf universal T-cell adapter-like enhancer intended to enable ADCC by engaging both antibody Fc and CD3 on T cells.
In the disclosed embodiment, the Fc-binding domain comprises the ectodomain of CD64, and the CD3-binding domain comprises an scFv comprising the variable light and variable heavy chains of an OKT3 monoclonal antibody. The OKT3 monoclonal antibody is specified as a dhOKT3 (deimmunized, humanized OKT3), forming a deimmunized, humanized CD3 binder within the fusion protein.
The fusion protein is further characterized by a flexible serine-glycine linker connecting the CD64 ectodomain and the dhOKT3 scFv, and by specific fusion protein sequences including SEQ ID NO:3. The document also describes use in an ADCC context where IgG4 antibodies are supported, including converting an IgG4 antibody such as Nivolumab from ADCC-negative to ADCC-positive via CD64 binding.
The background problem addressed is the need to amplify antibody-dependent cellular cytotoxicity by recruiting CD3+ T cells in the presence of antibody binding, including for antibody classes that may not otherwise provide ADCC.
Claims Coverage
The partial content provides two independent claims and several dependent refinements, resulting in inventive coverage of an Fc/CD3 dual-binding fusion protein. Across the claim set, the main inventive features are CD64 ectodomain-based Fc binding, a dhOKT3 scFv-based CD3 binding domain, optional linker-based structural definition, and optional sequence-level identity, plus a pharmaceutical composition including an excipient.
CD64 ectodomain Fc-binding fused to dhOKT3 scFv CD3-binding
A fusion protein comprising a binding domain for an antibody’s Fc fragment and a binding domain for CD3, wherein the Fc-binding domain comprises the ectodomain of CD64, and wherein the CD3-binding domain comprises an scFv comprising the VL and VH chains of an OKT3 monoclonal antibody, wherein the OKT3 monoclonal antibody is a dhOKT3 (deimmunized, humanized OKT3).
Serine-glycine linker connecting CD64 ectodomain and dhOKT3 scFv
The fusion protein wherein the CD64 ectodomain is fused to the dhOKT3 scFv via a flexible serine-glycine linker made of multiple serine and glycine residues.
CD64 ectodomain sequence identity (SEQ ID NO:1)
The fusion protein wherein the CD64 ectodomain has the amino acid sequence SEQ ID NO:1.
Linker plus dhOKT3 scFv sequence identity (SEQ ID NO:2)
The fusion protein wherein the flexible serine-glycine linker and the dhOKT3 scFv have the amino acid sequence SEQ ID NO:2.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition comprising the fusion protein and a pharmaceutically acceptable excipient.
Fusion protein defined by amino acid sequence SEQ ID NO:3
A fusion protein wherein said fusion protein comprises the amino acid sequence of SEQ ID NO:3.
Overall, the independent-claim coverage is directed to a dual-binding fusion protein that uses the ectodomain of CD64 as an Fc-binding domain and a deimmunized, humanized OKT3 (dhOKT3) scFv as a CD3-binding domain. Dependent refinements add a flexible serine-glycine linker and sequence-level definitions (SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3), and additional coverage includes a pharmaceutical composition with a pharmaceutically acceptable excipient.
Stated Advantages
Syngeneic/non-immunogenic approach.
Reduced antibody dose/side effects.
Off-the-shelf universal use.
Documented Applications
Recruitment of CD3+ T cells to antibody-coated diseased cells to crosslink CD3 and amplify antibody-dependent cellular cytotoxicity (ADCC).
Support for ADCC activity in the context of IgG4 antibodies, including converting Nivolumab from ADCC-negative to ADCC-positive via CD64 binding.
Use with multiple antibody-target systems described, including Rituximab/CD20, Herceptin/HER2, and Nivolumab/PD-1.
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