Human monoclonal antibody targeting TNFR2 for cancer immunotherapy
Inventors
Oppenheim, Joost J. • Dimitrov, Dimiter S. • Yang, De • Chen, Xin • Zhu, Zhongyu
Assignees
US Department of Health and Human Services
Publication Number
US-11389480-B2
Publication Date
2022-07-19
Expiration Date
2038-05-08
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Abstract
A human monoclonal antibody that specifically binds tumor necrosis factor receptor 2 (TNFR2), and a defucosylated form of the antibody, are described. The TNFR2-specific antibody was isolated from a human scFv phage display antibody library. The disclosed antibodies promote antibody-dependent cell-mediated cytotoxicity (ADCC) of human TNFR2+ CD4+ T regulatory cells in a dose- and time-dependent manner. Methods of using the TNFR2 antibodies, such as for tumor immunotherapy, are described.
Core Innovation
The invention concerns a human monoclonal antibody that specifically binds tumor necrosis factor receptor type 2 (TNFR2), including a defucosylated form of the antibody. These antibodies were isolated from a human single-chain variable fragment (scFv) phage display library. The disclosed antibodies promote antibody-dependent cell-mediated cytotoxicity (ADCC) of human TNFR2-positive CD4-positive regulatory T cells (Tregs) in a dose- and time-dependent manner. The antibodies include specific variable heavy (VH) and variable light (VL) domain complementarity determining region (CDR) sequences identified as SEQ ID NO: 1 and SEQ ID NO: 2, respectively.
The problem being addressed arises from TNFR2's role in cancer immunotherapy. TNFR2 is highly expressed on tumor-infiltrating immunosuppressive CD4+FoxP3+ regulatory T cells, which inhibit anti-tumor immune responses by promoting Treg activation and proliferation. Moreover, TNFR2 is expressed on some malignant cells where it promotes their survival and growth. Existing TNFR2-specific antibodies are antagonistic but do not efficiently induce ADCC. The invention solves this by providing a TNFR2-specific antibody that neither acts as an antagonist nor agonist but can efficiently induce ADCC of TNFR2+ Tregs, thereby promoting anti-tumor immune responses and direct killing of TNFR2-expressing tumor cells.
Claims Coverage
The patent claims encompass 41 claims including monoclonal antibodies, conjugates, compositions, detection methods, and therapeutic methods. The independent claims mainly cover the core antibody structure, its conjugates, and their uses.
Specific human monoclonal antibody binding TNFR2
A monoclonal antibody or antigen-binding fragment comprising a VH domain with CDRs of SEQ ID NO: 1 and a VL domain with CDRs of SEQ ID NO: 2 that specifically binds TNFR2.
Defucosylated antibody variant enhancing ADCC activity
A defucosylated form of the monoclonal antibody enhancing antibody-dependent cell cytotoxicity while having the same amino acid sequence as the parent antibody.
Immunoconjugate comprising the TNFR2 antibody and effector molecules
An immunoconjugate comprising the antibody or antigen-binding fragment linked to an effector molecule such as toxins including Pseudomonas exotoxin or detectable labels like fluorophores, enzymes, or radioisotopes.
Antibody-drug conjugate comprising the TNFR2 antibody and cytotoxic drugs
An ADC comprising the antibody conjugated to a drug, which can be a small molecule, anti-microtubule agent, anti-mitotic agent, or other cytotoxic agents.
Multi-specific antibodies incorporating the TNFR2 antibody
Multi-specific antibodies including bispecific and trispecific antibodies composed of the TNFR2 antibody combined with other antibodies binding T cell receptor components or NK cell activating receptors.
Antibody-nanoparticle conjugates for targeted delivery
Conjugates of the TNFR2 antibody with nanoparticles such as liposomes, dendrimers, micelles, or niosomes, optionally carrying cytotoxic agents.
Fusion proteins containing the TNFR2 antibody and heterologous proteins
Fusion proteins comprising the TNFR2 antibody and heterologous proteins or peptides, for example Fc proteins.
Methods of detecting TNFR2 expression using the antibody
Methods involving contacting a sample with the antibody and detecting binding, including using labeled antibodies or secondary antibodies for detecting TNFR2 expression.
Methods of promoting cell death of TNFR2+ CD4+ T regulatory cells
Methods promoting cell death of TNFR2-positive CD4+ Treg cells by contacting them with the antibody or administering the antibody to subjects.
Methods of enhancing anti-tumor response and treating TNFR2-positive cancers
Methods comprising administering the TNFR2 antibody or related compositions to subjects with tumors to enhance anti-tumor immune responses, treat TNFR2-positive cancers, and inhibit metastasis.
The claims cover a human monoclonal antibody specifically targeting TNFR2 with defined CDR sequences, including defucosylated forms and various conjugates such as immunoconjugates, ADCs, multi-specific antibodies, antibody-nanoparticle conjugates, and fusion proteins. Additionally, the claims include nucleic acids encoding these antibodies and methods for detection of TNFR2 and therapeutic methods for killing TNFR2+ T regulatory cells and treating TNFR2-positive cancers.
Stated Advantages
The antibody efficiently induces antibody-dependent cell-mediated cytotoxicity (ADCC) of TNFR2-positive CD4+ T regulatory cells, which previous TNFR2-specific antibodies did not achieve.
The defucosylated antibody variant shows enhanced ADCC activity compared to the fucosylated counterpart.
The antibody is capable of promoting anti-tumor immune responses by eliminating immunosuppressive T regulatory cells and directly killing TNFR2-expressing tumor cells.
Documented Applications
Use of the TNFR2-specific monoclonal antibody and its conjugates for cancer immunotherapy by promoting cell death of TNFR2+ CD4+ regulatory T cells and enhancing anti-tumor immune responses.
Method of treating TNFR2-positive cancers including ovarian cancer, colon cancer, renal cell carcinoma, multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.
Diagnostic methods for detecting and confirming TNFR2 expression in biological samples such as tissues or blood, to diagnose or confirm TNFR2-positive cancer.
Use of chimeric antigen receptors (CARs) incorporating TNFR2 antibodies for adoptive cell therapy targeting TNFR2-expressing tumors.
Conjugation of the antibody to therapeutic agents, diagnostic labels, chemotherapeutic agents, nanoparticles, and toxins for targeted delivery and treatment.
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