Guidance and Navigation Control proteins and method of making and using thereof
Inventors
Zhu, Yi • Olsen, Ole • Xia, Dong • JELLYMAN, David • BYKOVA, Katrina • ROUSSEAU, Anne-Marie • Brady, Bill • RENSHAW, Blair • Kovacevich, Brian • Liang, Yu • WANG, Camilla • Gao, Zeren • Huang, Hui
Assignees
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Publication Number
US-12029761-B2
Publication Date
2024-07-09
Expiration Date
Abstract
The application provides guidance and navigation control (GNC) proteins. In one embodiment, the guidance and navigation control (GNC) protein, comprising a binding domain for a T cell activating receptor, a binding domain for a tumor associated antigen, a bind domain for an immune checkpoint receptor, and a binding domain for a T cell co-stimulating receptor. The binding domain for the tumor associated antigen is not adjacent to the binding domain for the T cell co-stimulating receptor. In one embodiment, the binding domain for the T cell activating receptor is adjacent to the binding domain for the tumor associated antigen (TAA).
Core Innovation
The invention relates to guidance and navigation control (GNC) proteins configured as multi-specific antibody formats that bind a T cell activating receptor comprising CD3, a tumor associated antigen comprising EGFRvIII, CD19, or ROR1, an immune checkpoint receptor comprising PD-L1, and a T cell co-stimulating receptor comprising 4-1BB. The GNC protein includes distinct binding domains directed to CD3, a tumor associated antigen, PD-L1, and 4-1BB, integrating these binding specificities into a single protein.
A key spatial design feature is that the binding domain for the tumor associated antigen is not adjacent to the binding domain for the T cell co-stimulating receptor. The positioning of these domains is presented as a determinant of functional performance, and the document describes related antibody/Fc/linker architectures for implementing the binding domains.
The document frames the GNC protein as directing cytotoxic T cells to tumors while blocking inhibitory PD-L1 signaling and engaging co-stimulation through 4-1BB. Functional results described in the document report binding and redirected cytotoxicity, proliferation, cytokine IFNγ, and effector molecule granzyme B responses, with activity influenced by antigen binding domain positioning and functional contributions from the PD-L1 and 4-1BB domains.
Claims Coverage
The independent claim is clm-00001. It defines a GNC protein with four binding domains for CD3, a tumor associated antigen (EGFRvIII, CD19, or ROR1), PD-L1, and 4-1BB, and requires that the tumor-antigen binding domain is not adjacent to the 4-1BB co-stimulatory binding domain. Dependent claims refine antibody architecture and add additional constraints and composition-level definitions.
Multi-specific GNC protein with separated TAA and 4-1BB binding domains
A guidance and navigation control (GNC) protein comprising a binding domain for a T cell activating receptor wherein the T cell activating receptor comprises CD3; a binding domain for a tumor associated antigen wherein the tumor associated antigen comprises EGFRvIII, CD19, or ROR1; a binding domain for an immune checkpoint receptor wherein the immune checkpoint receptor comprises PD-L1; and a binding domain for a T cell co-stimulating receptor wherein the T cell co-stimulating receptor comprises 4-1 BB, wherein the binding domain for the tumor associated antigen is not adjacent to the binding domain for the T cell co-stimulating receptor.
The coverage centers on a multi-specific GNC protein that binds CD3, a selected tumor associated antigen, PD-L1, and 4-1BB, with a spatial separation requirement that the tumor associated antigen binding domain is not adjacent to the 4-1BB binding domain. Additional dependent refinements described in the provided material include antibody architecture, linker length, tandem N-terminal/C-terminal architecture with an IgG Fc domain, and specification of binding specificity using CDRs drawn from specified SEQ ID numbers.
Stated Advantages
Directing cytotoxic T cells to tumors.
Blocking inhibitory PD-L1 signaling.
Engaging co-stimulation through 4-1BB.
Documented Applications
A biological complex that includes a T cell with a T cell activating receptor and a T cell co-stimulating receptor, a cancer cell with a tumor associated antigen, and a GNC protein that binds to the T cell via the activating receptor and/or the co-stimulating receptor and binds to the cancer cell via the tumor associated antigen.
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