Antibodies
Inventors
Satijn, David • BREIJ, Esther C. W. • DE GOEIJ, Bart E. C. G. • KEMPER, Kristel • Engelberts, Patrick • Van Den Brink, Edward N. • RADEMAKER, Rik • VERZIJL, Dennis • HORBACH, Sjeng • Parren, Paul
Assignees
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Publication Number
US-11970544-B2
Publication Date
2024-04-30
Expiration Date
Abstract
The present invention relates to antibodies binding to 5T4, including bispecific antibodies binding to 5T4 and CD3. The invention further provides pharmaceutical compositions comprising the antibodies and use of the antibodies for therapeutic and diagnostic procedures, in particular in cancer therapy.
Core Innovation
The invention relates to nucleic acid constructs encoding antibodies that bind human 5T4. The encoded antibodies comprise a heavy chain variable (VH) region and a light chain variable (VL) region, where the VH region comprises the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 41, 42, and 43, respectively, and the VL region comprises the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 45, the sequence DAS, and SEQ ID NO: 46, respectively.
In further embodiments, the invention provides bispecific antibodies that bind to human 5T4 and human CD3. The bispecific antibody includes a first antigen-binding region for human 5T4 and a second antigen-binding region for human CD3, with specified variable heavy and variable light chain sequences set forth in SEQ ID NOs: 40, 44, 68, and 60, and comprises a human IgG1 Fc region with defined constant-region substitutions in the heavy chains, together with defined light chain constant-region sequences set forth in SEQ ID NOs: 95 and 96.
The nucleic acid constructs are further associated with expression vectors, host cells that comprise the constructs, and production of the encoded antibodies. The invention includes culturing the host cell in culture medium and purifying the antibody from the culture medium for both 5T4-binding antibodies and bispecific antibodies.
Claims Coverage
The document provides three independent claims covering nucleic acid constructs encoding a human 5T4-binding antibody with specified CDRs, and bispecific antibodies binding human 5T4 and human CD3 with specified VH/VL sequences and defined human IgG1 Fc residue substitutions. Each independent claim is further refined by dependent claims to expression vectors, host cells, and production by culturing and purifying from culture medium.
Nucleic acid construct encoding human 5T4-binding antibody with specified VH/VL CDRs
A nucleic acid construct, or combination of nucleic acid constructs, encoding an antibody which binds to human 5T4 and comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region comprises the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 41, 42, and 43, respectively, and the VL region comprises the CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NO: 45, the sequence DAS, and SEQ ID NO: 46, respectively.
Nucleic acid construct encoding 5T4/CD3 bispecific with specified 5T4 and CD3 VH/VL sequences and human IgG1 Fc residue substitutions
A nucleic acid construct, or combination of nucleic acid constructs, encoding a bispecific antibody comprising a first heavy chain and a first light chain comprising a first antigen-binding region which binds to human 5T4, and a second heavy chain and a second light chain comprising a second antigen-binding region which binds to human CD3, wherein the first antigen-binding region comprises a VH region comprising the amino acid sequence set forth in SEQ ID NO: 40 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 44; the second antigen-binding region comprises a VH region comprising the amino acid sequence set forth in SEQ ID NO: 68 and a VL region comprising the amino acid sequence set forth in SEQ ID NO: 60; the bispecific antibody comprises a human IgG1 Fc region; the first heavy chain comprises a constant region wherein the amino acid residues corresponding to L234, L235, D265 and F405 or K409 in a human IgG1 heavy chain according to EU numbering are F, E, A and L or R, respectively; and the first light chain and second light chain comprise light chain constant regions comprising the amino acid sequences set forth in SEQ ID NOs: 95 and 96, respectively.
Overall, claim coverage centers on nucleic acid constructs encoding a human 5T4-binding antibody with specified VH/VL CDR sequences and human 5T4/human CD3 bispecific antibodies with specified VH/VL sequences for each binding region, a human IgG1 Fc region with defined heavy-chain constant-region substitutions, and defined light chain constant regions.
Stated Advantages
Inert Fc variants are described as reducing Fc-mediated effector functions including PBMC CD69, C1q, and T-cell proliferation.
The described content includes reducing-condition hinge disulfide-bond isomerization for bispecifics.
Documented Applications
Therapeutic applications against 5T4+ cancers are described in the provided content.
Immunoconjugate/antibody-drug conjugate (ADC) use is described.
Companion diagnostic/propensity to respond is mentioned in the provided content.
Kits and anti-idiotypic antibodies (anti-Id antibodies) are mentioned in the provided content.
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