Tri-specific antibodies
Inventors
Zhu, Yi • Olsen, Ole • Xia, Dong • JELLYMAN, David • BYKOVA, Katrina • ROUSSEAU, Anne-Marie K. • Brady, Bill • RENSHAW, Blair • Kovacevich, Brian • Liang, Yu • Gao, Zeren
Assignees
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Publication Number
US-11649286-B2
Publication Date
2023-05-16
Expiration Date
Abstract
The application provides tri-specific antibody monomers having a N-terminal and a C-terminal, comprising in tandem from the N-terminal to the C-terminal, a first scFv domain at the N-terminal, a Fab domain, a Fc domain, and a second scFv domain at the C-terminal. In one embodiment, the first scFv domain, the Fab domain, and the second scFv domain each has a binding specificity against a different antigen.
Core Innovation
The invention relates to a tri-specific antibody monomer arranged in tandem from an N-terminal to a C-terminal, comprising a first scFv domain at the N-terminus, a Fab domain, an Fc domain, and a second scFv domain at the C-terminus. The first scFv domain has binding specificity against ROR1, PD-L1, EGFRvIII, or CD19, the Fab domain has binding specificity against PD-L1, EGFRvIII, or CD19, and the second scFv domain has binding specificity against CD3. The first scFv domain, the Fab domain, and the second scFv domain each bind a different antigen.
The invention further defines specific sequence options for the scFv and Fab binding specificities through pairs of sequences identified by SEQ ID NOs. For the first scFv domain, binding specificity is provided by specified pairs of sequences associated with ROR1, PD-L1, EGFRvIII, or CD19, and the Fab domain provides a corresponding binding specificity using specified pairs of sequences. For the second scFv domain binding to CD3, the antibody specifies one of multiple SEQ ID NO pairs associated with CD3 binding.
In example embodiments summarized in the provided patent content, the tri-specific antibody monomer architecture includes an N-terminal scFv, a central Fab, an IgG1 Fc, and a C-terminal scFv, with each domain targeting a different antigen including tumor-associated antigen targets such as ROR1, PD-L1, EGFRvIII, or CD19 together with an immune engager aspect using CD3. The content also describes a rationale versus checkpoint-driven resistance to bispecific T-cell engagers, and reports functional assays including binding and redirected T-cell cytotoxicity assays using tumor targets and immune effectors.
Claims Coverage
The provided independent claims are clm-00001 and clm-00017. Across these, the inventive coverage is anchored by a tandem tri-specific antibody monomer architecture with selectable domain binding specificities and defined CDR/sequence-set constraints, including explicit targeting of CD3 for the C-terminal scFv and selectable antigen targeting for the N-terminal scFv and the middle Fab.
Tandem tri-specific antibody monomer architecture with distinct antigen-binding domains
A tri-specific antibody monomer having a N-terminal and a C-terminal, comprising in tandem from the N-terminal to the C-terminal a first scFv domain at the N-terminal, a Fab domain, an Fc domain, and a second scFv domain at the C-terminal, wherein the first scFv domain, the Fab domain, and the second scFv domain each has a binding specificity against a different antigen.
N-terminal first scFv binding specificity to a selectable antigen set with specified SEQ ID NO pairs
The first scFv domain at the N-terminal having a binding specificity against ROR1, PD-L1, EGFRvIII, or CD19, comprising one of the following pairs of sequences SEQ ID NOs: (2 and 4), or (6 and 8), or (10 and 12), for ROR1; SEQ ID NOs (14 and 16) for PD-L1; SEQ ID NOs (40 and 42) for EGFRvIII; and SEQ ID NOs (44 and 46) for CD19.
Middle Fab binding specificity to a selectable antigen set with specified SEQ ID NO pairs
The Fab domain having a binding specificity against PD-L1, EGFRvIII, or CD19 and comprising the respective pair of sequences SEQ ID NOs: (14 and 16), or (40 and 42), or (44 and 46).
C-terminal second scFv binding specificity to CD3 with selectable SEQ ID NO pairs
A second scFv domain at the C-terminal, having a binding specificity against CD3, comprising one the following pairs of sequences SEQ ID NOs: (18 and 20), (22 and 24), (26 and 28), (30 and 32), (30 and 34).
CDR-set constrained tri-specific antibody monomer with selectable alternative CDR pairs
A tri-specific antibody monomer comprising an amino acid sequence of 3 complementarity determining regions (CDRs) of SEQ ID NO: 14 and 3 CDRs of SEQ ID NO: 16, and one of: 3 CDRs of SEQ ID NO: 6 and 3 CDRs of SEQ ID NO: 8, 3 CDRs of SEQ ID NO: 40 and 3 CDRs of SEQ ID NO: 42, and 3 CDRs of SEQ ID NO: 44 and 3 CDRs of SEQ ID NO: 46, wherein the tri-specific antibody monomer comprises 3 CDRs of SEQ ID NO: 22 and 3 CDRs of SEQ ID NO: 24.
Overall, the independent claims cover a tandem tri-specific antibody monomer with an N-terminal first scFv, a middle Fab, an Fc domain, and a C-terminal second scFv, where each domain binds a different antigen. The coverage is further constrained by selectable SEQ ID NO pairs for binding specificities and, in clm-00017, by specified CDR sets including fixed SEQ ID NO: 14/16 and SEQ ID NO: 22/24 along with one selectable alternative CDR-pair set.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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