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-9676846-B2
Publication Date
2017-06-13
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
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 IgG and scFv formats, and bispecific forms of these antibodies are also provided. Nucleic acids encoding these antibodies, vectors including these nucleic acids, and host cells transformed with these vectors are disclosed. Pharmaceutical compositions comprising these antibodies are described, along with methods for treating subjects with cancer and for inhibiting phosphorylation of the insulin-like growth factor-I receptor.
The problem being solved arises from the role of the insulin-like growth factor (IGF) system, including IGF-I, IGF-II, and the IGF-I receptor (IGF-IR), in cancer. IGF-mediated signaling promotes cell transformation, proliferation, survival, motility, and migration. Elevated levels of IGF-I are epidemiologically associated with increased risk for various common cancers. Targeting IGF system components has been shown to affect these processes, yet improved multi-target therapies for treating neoplastic and metastatic cancers are needed. The human monoclonal antibodies disclosed aim to specifically bind both IGF-I and IGF-II with high affinity to potently inhibit IGF-IR signaling and thus provide enhanced therapeutic approaches.
Claims Coverage
The patent includes multiple independent claims covering isolated nucleic acid molecules encoding single chain Fv proteins (scFv) and heavy or light chain variable regions, expression vectors comprising these nucleic acids, transformed host cells, methods of producing scFv, and compositions comprising these nucleic acids.
Isolated nucleic acid encoding scFv with defined heavy and light chain variable regions
An isolated nucleic acid molecule encoding a scFv comprising a heavy chain variable region with amino acids 26-33, 51-58, and 97-109 of SEQ ID NO: 7, where residue 56 is G and residue 109 is N, and a light chain variable region comprising amino acids 27-32, 50-52, and 89-97 of SEQ ID NO: 8, that specifically binds IGF-II and IGF-I with equilibrium dissociation constants of 200 pM or less.
Expression vector and transformed host cell comprising nucleic acid encoding specific scFv
Expression vectors comprising the isolated nucleic acid molecule encoding the defined scFv and host cells transformed with such vectors.
Isolated nucleic acid encoding heavy chain variable region forming human monoclonal antibody
Nucleic acid encoding a heavy chain variable region comprising amino acids 26-33, 51-58, and 97-109 of SEQ ID NO: 7 with residues 56 G and 109 N, which forms a human monoclonal antibody or antigen binding fragment binding IGF-II and IGF-I with Kd of 200 pM or less.
Isolated nucleic acid encoding light chain variable region forming human monoclonal antibody
Nucleic acid encoding a light chain variable region comprising amino acids 27-32, 50-52, and 89-97 of SEQ ID NO: 8 forming a human monoclonal antibody or antigen binding fragment binding IGF-II and IGF-I with Kd of 200 pM or less.
The claims cover isolated nucleic acid molecules encoding the precise heavy and light chain variable regions or scFv proteins, expression vectors including these nucleic acids, host cells transformed with these vectors, methods for producing the scFv, and pharmaceutical compositions comprising these molecules, all providing specific binding to IGF-I and IGF-II with high affinity.
Stated Advantages
Human monoclonal antibodies with picomolar affinity specifically bind both IGF-I and IGF-II and potently inhibit IGF-IR signal transduction function.
The antibodies are active in multiple formats, including IgG and scFv, and retain high affinity upon conversion to IgG, supporting stability and extended half-life in vivo.
The antibodies inhibit IGF-IR and insulin receptor phosphorylation induced by IGF-I and IGF-II, thereby effectively blocking tumor cell proliferation in vitro.
Bispecific antibody forms combining different epitope recognition sites show synergistic effects, improved binding, and enhanced inhibition of receptor phosphorylation.
Documented Applications
Treatment of subjects with cancer, including various types such as sarcoma, leukemia, prostate cancer, lung cancer, breast cancer, colon cancer, stomach cancer, uterine cancer, cervical cancer, esophageal cancer, liver cancer, pancreatic cancer, kidney cancer, thyroid cancer, brain cancer, ovarian cancer, multiple myeloma, and neurodegenerative and autoimmune disorders.
Methods for inhibiting phosphorylation of the insulin-like growth factor-I receptor in cells to interfere with tumor growth.
Diagnostic methods for detecting IGF-I and IGF-II in biological samples to diagnose malignancy or determine prognosis.
Use in immunoassays, including ELISA, FACS, Western blots, and immunohistochemistry, and kits for detecting IGF-I and IGF-II expression in tissues and fluids.
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