Human monoclonal antibodies that bind insulin-like growth factor (IGF) I and II
Inventors
Dimitrov, Dimiter S. • Zhu, Zhongyu • Zhao, Qi
Assignees
US Department of Health and Human Services
Publication Number
US-9150644-B2
Publication Date
2015-10-06
Expiration Date
2032-04-11
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Abstract
Disclosed herein are human monoclonal antibodies that specifically bind both IGF-I and IGF-II with picomolar affinity and potently inhibit the IGF-IR signal transduction function. These antibodies are active in both an IgG and a scFv format. Bispecific forms of these antibodies are also disclosed. Nucleic acids encoding these antibodies, vectors including these nucleic acids, and host cells transformed with these vectors are also disclosed herein. Also disclosed are pharmaceutical compositions including these antibodies. Methods are provided for treating a subject with cancer and for inhibiting phosphorylation of the insulin-like growth factor-I receptor. Methods are also provided for diagnosing cancer.
Core Innovation
The invention disclosed in this patent consists of human monoclonal antibodies that specifically bind both insulin-like growth factor I (IGF-I) and insulin-like growth factor II (IGF-II) with picomolar affinity, potently inhibiting the signal transduction function of the IGF-I receptor (IGF-IR). These antibodies are active in both immunoglobulin G (IgG) and single chain fragment variable (scFv) formats. Additionally, bispecific forms of these antibodies are disclosed, as well as nucleic acids encoding these antibodies, vectors containing these nucleic acids, and host cells transformed with such vectors. Pharmaceutical compositions including these antibodies are also described, alongside methods for treating subjects with cancer, inhibiting phosphorylation of IGF-IR, and diagnosing cancer.
The problem addressed by this invention arises from the established role of the insulin-like growth factor system, including IGF-IR and its ligands IGF-I and IGF-II, in physiologic and pathologic processes such as cancer. Prior approaches targeting the IGF system have had limitations, and there remains a need for improved multi-target therapies to treat neoplastic disease and metastatic cancers. High circulating levels of IGF-I correlate with increased cancer risk across several common cancer types. Although inhibition of IGF-IR signaling is recognized to have proapoptotic and antiproliferative effects, effective therapeutics addressing both ligands with high affinity that potently inhibit IGF-IR phosphorylation and cancer cell growth have been lacking.
The invention provides novel human monoclonal antibodies that bind IGF-I and IGF-II with equilibrium dissociation constants of 200 pM or less and inhibit phosphorylation of the insulin-like growth factor receptor, thereby inhibiting cancer cell proliferation and motility. These antibodies have been affinity matured and shown to function effectively in vitro to inhibit phosphorylation of IGF-IR and insulin receptor, and to suppress cancer cell growth. Bispecific antibodies combining these antibodies with others targeting IGF-II alone exhibit synergistic binding and inhibition effects. Thus, the core innovation is the generation and characterization of high-affinity, dual-binding human monoclonal antibodies that effectively inhibit IGF-IR mediated signaling relevant to cancer therapy and diagnosis.
Claims Coverage
The patent claims encompass seven main inventive features focusing on the structure, binding properties, formats, and therapeutic and diagnostic uses of the human monoclonal antibodies and bispecific antibodies that bind IGF-I and IGF-II with high affinity.
Human monoclonal antibody variable region sequences
The isolated human monoclonal antibody or antigen binding fragment comprises a heavy chain variable region including amino acids 26-33, 51-58, and 97-109 of SEQ ID NO: 7, with residue 56 as glycine (G) and residue 109 as asparagine (N); and a light chain variable region including amino acids 27-32, 50-52, and 89-97 of SEQ ID NO: 8. This antibody specifically binds IGF-II and IGF-I with dissociation constants of 200 pM or less.
Antibody isotype variants
The antibody can be of the IgG or IgM isotype, including specifically IgM or IgG4 subclasses.
Antigen binding fragment formats
The antigen binding fragment of the antibody can be Fab′, F(ab)′2, single-chain Fv (scFv), or disulfide stabilized Fv (dsFv) fragments.
Bispecific antibody combining IGF-I/IGF-II and IGF-II specificity
An isolated bispecific antibody comprises a first monoclonal antibody or fragment as above (binding IGF-I and IGF-II) and a second monoclonal antibody or fragment with heavy chain variable region amino acids 26-33, 51-58, and 97-109 of SEQ ID NO: 23 and light chain variable region amino acids 27-32, 50-52, and 89-98 of SEQ ID NO: 24, specifically binding IGF-II.
Labeling for detection
The monoclonal antibody or antigen binding fragment can be labeled with detectable labels including fluorescent, enzymatic, or radioactive labels for diagnostic purposes.
Binding affinity specifics
The antibody binds IGF-I with a Kd of 200 pM or less and binds IGF-II with a Kd of 60 pM or less.
Therapeutic and diagnostic methods
Compositions comprising these antibodies and pharmaceutically acceptable carriers are claimed, along with methods of detecting IGF-I and/or IGF-II in biological samples, inhibiting IGF-IR phosphorylation, and treating breast cancer by administering a therapeutically effective amount of these compositions to reduce tumor burden or metastasis.
The claims comprehensively cover human monoclonal antibodies and antigen binding fragments with defined variable region sequences that bind IGF-I and IGF-II with high affinity, their use in bispecific antibody formats targeting IGF-II, labeling for diagnostics, and therapeutic compositions and methods for inhibiting IGF-IR signaling and treating cancer.
Stated Advantages
The antibodies potently inhibit IGF-IR signal transduction, resulting in effective blocking of cancer cell proliferation and motility in vitro.
The human monoclonal antibodies bind IGF-I and IGF-II with picomolar affinity, offering high specificity and efficacy.
The antibodies are active in multiple formats including IgG, scFv, and bispecific forms, providing versatility in therapeutic and diagnostic applications.
Bispecific antibodies exhibit synergistic effects in binding and inhibition of IGFs, improving therapeutic potential.
Human origin of the antibodies reduces immunogenicity compared to murine antibodies, decreasing the risk of human anti-murine antibody (HAMA) response.
Documented Applications
Treatment of cancer including breast cancer, prostate cancer, glioma, fibrosarcoma, lung cancer, colon cancer, and ovarian cancer.
Inhibition of phosphorylation of the insulin-like growth factor-I receptor to suppress IGF-IR mediated signal transduction in cancer cells.
Diagnostic detection of IGF-I and IGF-II in biological samples to assess cancer presence or prognosis.
Use as compositions comprising antibodies or nucleic acids for therapeutic administration to inhibit tumor growth and metastasis.
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