Anti Notch-1 antibodies
Inventors
Li, Kang • Wei, Ping • Peng, Qinghai • Lippincott, John Andrew • Stone, Donna Marie • Hostomsky, Zdenek
Assignees
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Publication Number
US-9090690-B2
Publication Date
2015-07-28
Expiration Date
Abstract
This invention is directed toward monoclonal antibodies that bind specifically to Notch1. In one embodiment, the antibodies binds to at least a first epitope and a second epitope, wherein the first epitope resides with the LinA domain of the Notch1 negative regulatory region (NRR), and the second epitope resides within the HD-C domain of the Notch1 NRR.
Core Innovation
The invention relates to isolated antibodies, or antigen binding portions thereof, that specifically bind human Notch-1. The antibodies bind to at least a first epitope and a second epitope, with the first epitope comprising amino acid residues taken from SEQ ID NO: 23 and the second epitope comprising amino acid residues taken from SEQ ID NO: 31. The targeted epitope regions are located in the Notch-1 negative regulatory region (NRR), including a first epitope within the Lin-A domain and a second epitope within the HD-C domain.
The disclosure characterizes binding through defined major epitopes and reports affinity using equilibrium dissociation constant (K_D) thresholds. It further provides cross-competition concepts, antibody variable region CDR sequence sets, and functional data showing that inhibition of Notch signaling is associated with reduction of NICD and suppression of Hes1 and Hes4.
The invention also provides antibody sequence-definition examples in terms of heavy chain variable region CDR1, CDR2, and CDR3 sequences, together with light chain variable region CDR1, CDR2, and CDR3 sequences. The disclosure further describes antibody formats including humanized, human, fully human, chimeric, or mouse antibodies, and recites use in treating Notch-1–associated cancers, including cancer cell growth inhibition in cancer models cited in the disclosure.
Claims Coverage
The independent claims cover three distinct antibody definitions, each grounded in human Notch-1 binding. Across these independent claims, the inventive aspects focus on epitope-defined dual-epitope binding and specific heavy-chain and light-chain CDR sequence sets.
Dual-epitope human Notch-1 binding with SEQ ID NO: 23 first epitope and SEQ ID NO: 31 second epitope residue selection
An isolated antibody, or an antigen binding portion thereof, that specifically binds to human Notch-1, wherein the antibody or antigen binding portion binds to at least a first epitope and a second epitope, wherein the first epitope comprises 1 to 4 amino acid residues selected from amino acid residues 15, 17, 18, and 19 of SEQ ID NO: 23, and wherein the second epitope comprises 1 to 5 amino acid residues of SEQ ID NO: 31.
Dual-epitope human Notch-1 binding with constrained SEQ ID NO: 31 second-epitope positions
An isolated antibody, or an antigen binding portion thereof, that specifically binds to human Notch-1, wherein the antibody or antigen binding portion binds to at least a first epitope and a second epitope, wherein the first epitope comprises 1 to 4 amino acid residues of SEQ ID NO: 23, and wherein the second epitope comprises 1 to 5 amino acid residues selected from amino acid residues 3, 4, 5, 7, and 8 of SEQ ID NO: 31.
CDR sequence-defined antibody binding to human Notch-1 using specified heavy- and light-chain CDR sequences
An isolated antibody, or an antigen binding portion thereof, that specifically binds to human Notch-1, comprising heavy chain variable region CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 18, 19, and 20, and light chain variable region CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 12, 13, and 14.
Overall, the independent claims define human Notch-1–binding antibodies either by dual-epitope binding with residue constraints on SEQ ID NO: 23 and SEQ ID NO: 31, or by specified heavy- and light-chain CDR amino acid sequences.
Stated Advantages
Inhibition of Notch signaling is associated with reduction of NICD and suppression of Hes1 and Hes4.
Inhibition of cancer cell growth is reported for the disclosed antibodies in cited cancer models and cell lines.
Documented Applications
Treating cancer in a subject by administering a therapeutically effective amount of the antibody (or antigen binding portion) or a pharmaceutical composition containing it, where the cancer is T-cell acute lymphoblastic leukemia (T-ALL) or breast cancer.
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