Antibodies and methods of use thereof
Inventors
van Dijk, Marc • Mundt, Cornelia Anne • Ritter, Gerd • Schaer, David • Wolchok, Jedd David • Merghoub, Taha • Wilson, Nicholas Stuart • Savitsky, David Adam • Findeis, Mark Arthur • Zappasodi, Roberta • Holmgaard, Rikke Bæk • HOLMGAARD, RIKKE BAEK, null • Cuillerot, Jean-Marie • Proscurshim, Igor • Shebanova, Olga
Assignees
Ludwig Institute for Cancer Research Ltd • Memorial Sloan Kettering Cancer Center • Agenus Inc
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Publication Number
US-11993653-B2
Publication Date
2024-05-28
Expiration Date
Abstract
Provided are antibodies that specifically bind to CTLA-4 and/or PD-1 and antagonize CTLA-4 and/or PD-1 function. Also provided are pharmaceutical compositions and kits 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 either alone or in combination.
Core Innovation
The invention provides a therapeutic combination for increasing T cell activation in a subject that has cancer by administering an effective amount of a first isolated antibody that specifically binds human CTLA-4 and a second isolated antibody that specifically binds human PD-1. The method is defined by antibody binding specificity to the CTLA-4 and PD-1 signaling checkpoints and by CDRH1, CDRH2, and CDRH3 of the VH sequence and CDRL1, CDRL2, and CDRL3 of the VL sequence using specified SEQ ID NO combinations.
The first isolated antibody comprises a heavy chain variable region VH with the CDRH1, CDRH2, and CDRH3 of the VH amino acid sequence of SEQ ID NO: 1 and a light chain variable region VL with the CDRL1, CDRL2, and CDRL3 of the VL amino acid sequence of SEQ ID NO: 14. The second isolated antibody comprises a VH with the CDRH1, CDRH2, and CDRH3 of the VH amino acid sequence of SEQ ID NO: 66 and a VL with the CDRL1, CDRL2, and CDRL3 of the VL amino acid sequence of SEQ ID NO: 74.
The invention is further positioned for specific cancer settings, including cervical cancer and contexts defined by patient and tumor characteristics in dependent claims. For cervical cancer, the method is used in a subject with relapsed disease after platinum-based chemotherapy and/or in advanced or metastatic disease. The document also discusses multispecific antibody formats, Fc region engineering options, and pharmaceutical composition context in cancer.
Claims Coverage
The provided claims include two independent claims. Coverage centers on increasing T cell activation using a therapeutic combination of an anti-CTLA-4 antibody and an anti-PD-1 antibody, with two inventive features defining the antibodies by specified CDR sequences and a further cervical cancer limitation in the second independent claim.
Therapeutic combination of CTLA-4 and PD-1 binding antibodies
Administering to a cancer subject an effective amount of a therapeutic combination comprising a first isolated antibody that specifically binds to human CTLA-4 and a second isolated antibody that specifically binds to human PD-1, for increasing T cell activation.
CTLA-4 antibody defined by SEQ ID NO: 1/14 CDR regions
The first isolated antibody comprises a heavy chain variable region VH with CDRH1, CDRH2, and CDRH3 of the VH amino acid sequence of SEQ ID NO: 1, and a light chain variable region VL with CDRL1, CDRL2, and CDRL3 of the VL amino acid sequence of SEQ ID NO: 14.
PD-1 antibody defined by SEQ ID NO: 66/74 CDR regions
The second isolated antibody comprises a heavy chain variable region VH with CDRH1, CDRH2, and CDRH3 of the VH amino acid sequence of SEQ ID NO: 66, and a light chain variable region VL with CDRL1, CDRL2, and CDRL3 of the VL amino acid sequence of SEQ ID NO: 74.
Cervical cancer patient context
Administering to a subject that has cervical cancer an effective amount of the therapeutic combination comprising the first isolated CTLA-4 binding antibody and the second isolated PD-1 binding antibody as defined by the CDR-defined VH and VL sequence requirements.
The claims cover a combination therapy that increases T cell activation in a cancer subject using two isolated antibodies that specifically bind human CTLA-4 and human PD-1. The defining inventive boundaries are the CDRH1/H2/H3 and CDRL1/L2/L3 sequence requirements for each antibody using the specified SEQ ID NO: 1/14 and SEQ ID NO: 66/74 variable-region amino acid sequences, with the second independent claim further limited to cervical cancer.
Stated Advantages
Increases T cell activation in a subject that has cancer.
Reduces CTLA-4 activity and/or PD-1 activity, including ligand binding and associated immune readouts such as cytokine inhibition/production and T-cell proliferation.
Documented Applications
Treating a subject that has cancer by increasing T cell activation using a therapeutic combination comprising an anti-CTLA-4 antibody and an anti-PD-1 antibody.
A subject that has cervical cancer.
Relapsed disease after platinum-based chemotherapy.
Advanced or metastatic cervical cancer.
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