Anti-mesothelin antigen-binding molecules and uses thereof
Inventors
Correnti, Colin • Mehlin, Christopher • Meininger, David • Bandaranayake, Ashok
Assignees
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Publication Number
US-11981745-B2
Publication Date
2024-05-14
Expiration Date
Abstract
The present disclosure provides antibodies and polypeptides that specifically bind to mesothelin (MSLN), including bispecific antibodies that bind both MSLN and a T cell antigen (e.g., CD3). Also provided are pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies.
Core Innovation
The invention relates to isolated antibody molecule(s) that specifically bind human mesothelin (human MSLN). The antibody molecule comprises a VH with CDRs CDRH1, CDRH2, and CDRH3, and a VL with CDRs CDRL1, CDRL2, and CDRL3, with the CDR amino acid sequences defined by SEQ ID NOs: 3, 30, 5, 6, 7, and 35.
A further aspect defines an isolated antibody molecule that specifically binds human MSLN using defined heavy-chain and light-chain amino acid sequences. The heavy chain and light chain are set forth in SEQ ID NOs 83 and 47, respectively, or in SEQ ID NOs 84 and 47, respectively.
The disclosure further specifies antibody formats including architectures that include a CD3 binding moiety. In embodiments, the CD3 binding moiety is covalently linked to the C-terminus of the light chain through a peptide linker, and the CD3 binding moiety is an antibody or a single-chain fragment variable (scFv). The antibody molecules also include heavy-chain constant-region selection among human IgG and IgA types, variants with lower FcγR binding affinity relative to wild-type, and conjugation to payloads including cytotoxic or cytostatic agents, toxins, radionuclides, or detectable labels.
Claims Coverage
The independent claim scope includes 2 inventive features, directed to isolated antibody molecules that specifically bind human MSLN and are defined either by explicit VH/VL CDR amino-acid sequences or by explicit heavy- and light-chain amino-acid sequences. Dependent claims extend the scope to CD3 binding moiety embodiments, covalent linkage to the light-chain C-terminus through a peptide linker, selected CD3-binding moiety types, heavy-chain constant-region classes, FcγR-affinity variants, and conjugation to specified payload or label categories.
Isolated human MSLN-binding antibody with specified VH and VL CDR sequences
An isolated antibody molecule specifically binding human MSLN, comprising a VH with CDRs CDRH1, CDRH2, and CDRH3 and a VL with CDRs CDRL1, CDRL2, and CDRL3, wherein the CDR sequences comprise the amino acid sequences set forth in SEQ ID NOs: 3, 30, 5, 6, 7, and 35, respectively.
Isolated human MSLN-binding antibody with defined heavy- and light-chain sequences
An isolated antibody molecule that specifically binds human MSLN, comprising a heavy chain and a light chain comprising amino acid sequences set forth in SEQ ID NOs: 83 and 47, respectively, or SEQ ID NOs: 84 and 47, respectively.
CD3 binding moiety covalently linked to light-chain C-terminus via peptide linker
The CD3 binding moiety is covalently linked to the C-terminus of the light chain through a peptide linker, optionally containing an amino acid sequence from SEQ ID NO: 63, 64, 73, 74, or 75.
CD3 binding moiety provided as antibody or scFv
A CD3 binding moiety is either an antibody or a single-chain fragment variable (scFv).
FcγR-modified heavy-chain constant region with lower FcγR binding affinity
The heavy chain constant region contains a specified amino-acid sequence (SEQ ID NO: 53, 54, 55, 56, or 72) and/or is a wild-type variant that binds FcγR with lower affinity than the wild-type heavy chain constant region.
Human IgG/IgA heavy-chain constant-region class selection
The antibody heavy chain constant region is selected from human IgG1, human IgG2, human IgG3, human IgG4, human IgA1, or human IgA2.
Conjugation to cytotoxic, cytostatic, toxin, radionuclide, or detectable label payload categories
The isolated antibody molecule is conjugated to one of a cytotoxic agent, cytostatic agent, toxin, radionuclide, or detectable label.
Overall, the claim set covers isolated MSLN-binding antibodies defined by specified CDR and/or heavy/light chain amino-acid sequence sets, with additional scope for MSLN/CD3 bispecific architectures, constant-region class and FcγR-affinity variants, and conjugate payload or label categories.
Stated Advantages
Improved biodistribution/tissue retention is aimed for by having an advantage of high isoelectric point and unexpectedly fast serum clearance in human FcRn knock-in mice.
Documented Applications
Treatment and combination-use scope for cancers is described, associated with MSLN and CD3 targeting.
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