Antibodies to M(H)DM2/4 and their use in diagnosing and treating cancer
Inventors
Sarafraz-Yazdi, Ehsun • Evans, Brad R.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11407840-B2
Publication Date
2022-08-09
Expiration Date
Abstract
The present invention relates to certain anti-M(H)DM2/4 antibodies or antigen-binding fragments thereof, pharmaceutical compositions comprising anti-M(H)DM2/4 antibodies or antigen-binding fragments thereof, antibody-drug conjugates comprising anti-M(H)DM2/4 antibodies or antigen-binding fragments thereof bound to a cytotoxic drug, and the use of such antibodies, fragments, compositions and conjugates for treating cancer and/or for preventing metastases. In particular, described herein are certain antibodies or antigen-binding fragments thereof that specifically bind to extracellularly accessible epitopes of M(H)DM2/4 and inhibit tumor growth in vivo, pharmaceutical compositions comprising such antibodies or fragments, antibody-drug conjugates comprising such antibodies or fragments, and the use of such antibodies, fragments, compositions and conjugates for treating cancer or for preventing metastasis.
Core Innovation
The invention relates to an antibody or an antigen-binding fragment that binds to M(H)DM2/4, including HDM2/MDM2 and/or HDM4/MDM4, in a subject. The antibody or antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, with VHCDR1, VHCDR2, and VHCDR3 corresponding to a VH amino acid sequence of SEQ ID NO:36 and VLCDR1, VLCDR2, and VLCDR3 corresponding to a VL amino acid sequence of SEQ ID NO:37.
The antibody or antigen-binding fragment binds to an extracellularly accessible epitope on intact cancer cells, including an epitope represented by the peptide sequence MCNTNMSVPTDGAVT (SEQ ID NO:1). The disclosure also describes monoclonal and multispecific/bispecific antibody formats, humanized options, and antigen-binding fragments including scFv, Fv, Fab, F(ab’)2, and sdFv.
The invention is described in the context of antibodies that are optionally not bound to cell-penetrating peptides and/or not conjugated to cytotoxic drugs. Mechanisms of effector-mediated cytotoxicity including complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity are also described, together with selective binding to intact cancer cells versus normal PBMCs and combination synergy with gemcitabine and nab-paclitaxel.
Claims Coverage
The claim coverage centers on a method of treating a subject with cancer expressing M(H)DM2/4. The inventive features are the defined M(H)DM2/4-binding antibody or antigen-binding fragment and its VH/VL CDR sequences corresponding to SEQ ID NO:36 and SEQ ID NO:37, with additional refinements including extracellular epitope targeting and CDC/ADCC-related configuration.
Treating cancer expressing M(H)DM2/4 with a defined M(H)DM2/4-binding antibody
A method of treating a cancer expressing M(H)DM2/4 in a subject in need thereof by administering a composition comprising an antibody or an antigen-binding fragment thereof that binds to M(H)DM2/4, wherein the antibody or antigen-binding fragment comprises a VH with VHCDR1, VHCDR2, and VHCDR3 corresponding to the CDRs of a VH having the amino acid sequence of SEQ ID NO:36, and a VL with VLCDR1, VLCDR2, and VLCDR3 corresponding to the CDRs of a VL having the amino acid sequence of SEQ ID NO:37.
Extracellularly accessible epitope binding to a specific M(H)DM2/4 peptide
The antibody or antigen-binding fragment binds to an extracellularly accessible epitope of M(H)DM2/4 represented by the peptide sequence MCNTNMSVPTDGAVT (SEQ ID NO:1).
CDR sequence definition across VH/VL numbering systems
The antibody or antigen-binding fragment includes VHCDR1, VHCDR2, and VHCDR3 and VLCDR1, VLCDR2, and VLCDR3, with specified amino-acid sequences defined under Chothia, AbM, Kabat, Contact, and IMGT systems.
Sequence identity thresholds for VH and VL
The antibody or antigen-binding fragment comprises a VH with at least 70% sequence identity to SEQ ID NO:36 and a VL with at least 70% sequence identity to SEQ ID NO:37.
CDC/ADCC functional mechanism without cytotoxic drug conjugation
The antibody or antigen-binding fragment mediates complement-dependent cytotoxicity or antibody-dependent cell-mediated cytotoxicity, and is not conjugated to a cytotoxic drug.
Solid cancer treatment limited to specified cancer types
The solid cancer being treated is one of lung cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, melanoma, breast cancer, colon cancer, bladder cancer, astrocytic neoplasm, glioblastoma, or pediatric Rhabdomyosarcoma.
The claimed coverage is directed to administering an M(H)DM2/4-binding antibody or antigen-binding fragment defined by VH/VL CDRs tied to SEQ ID NO:36 and SEQ ID NO:37. The coverage further includes extracellular epitope targeting, sequence identity constraints, CDC/ADCC-related configuration without cytotoxic drug conjugation, and a defined list of solid cancer types.
Stated Advantages
Selective binding to intact cancer cells versus normal PBMCs.
Growth inhibition and CDC-mediated cytotoxicity in vitro.
In vivo anti-tumor efficacy in syngeneic mouse models.
Synergy with gemcitabine and nab-paclitaxel in the described models.
Evidence for long-term anti-tumor immunity.
Provides strong anti-tumor activity in vivo.
Provides long-term immunity, with mice remaining tumor-free after cessation of treatment.
Resists tumor re-challenge.
Reduces tumor burden in advanced Panc-2 tumors after a single i.p. dose.
Exhibits dose-dependent effect in the MC-38 model.
Supports improved anti-tumor performance of a chimeric NMC-303 IgG1 compared to control in CT-26.
Provides mechanistic rationale via extracellularly accessible M(H)DM2/4 epitopes enabling immune activation and a combination rationale with chemotherapy exploiting increased plasma membrane M(H)DM2/4.
Documented Applications
Treating a cancer expressing M(H)DM2/4 in a subject in need thereof.
Treatment of solid cancers including lung cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, melanoma, breast cancer, colon cancer, bladder cancer, astrocytic neoplasm, glioblastoma, and pediatric Rhabdomyosarcoma.
Combination use with gemcitabine and nab-paclitaxel for anti-tumor efficacy in the described syngeneic mouse models.
Diagnostic/companion diagnostic concepts based on binding to intact cells.
Used in in vivo mouse studies for anti-tumor activity and long-term immunity against tumor challenges, including re-challenge resistance.
Pancreatic cancer model use is described, including Panc-2 tumors and an i.p. dosing study.
MC-38 model is described as showing a dose-dependent effect.
CT-26 tumor model is described for comparative efficacy of a chimeric NMC-303 IgG1 versus control.
Combination use with gemcitabine/nab-paclitaxel (G+nP) is described in mouse studies.
Interested in licensing this patent?