New anti-IGF-IR antibodies and their applications

摘要

An isolated antibody (Ab), and its functional fragments, that bind to human insulin-like growth factor-1 receptor (IGF-1R) and optionally: (i) inhibit natural binding of insulin-like growth factors (IGF)-1 and/or -2; and/or (ii) inhibit specifically tyrosine kinase activity of IGF-1R. An isolated antibody (Ab), and its functional fragments, that bind to human insulin-like growth factor-1 receptor (IGF-1R) and optionally inhibit natural binding of insulin-like growth factors (IGF)-1 and/or -2 and/or inhibit specifically tyrosine kinase activity of IGF-1R, is new. Ab comprises: (a) a light chain containing at least one complementarity-determining region (CDR) of one of 3 fully defined sequences comprising 16, 7 or 9 amino acids as given in the specification; or (b) a heavy chain containing at least one of the CDRs of one of 3 fully defined sequences comprising 6, 16 or 8 amino acids as given in the specification or sequences with 80% identity after optimal alignment. Independent claims are also included for the following: (1) murine hybridomas that secrete Ab; (2) an isolated nucleic acid (I) that: (a) is RNA or DNA and encodes Ab or its fragments; (b) is the complement of (a); or (c) has at least 18 nucleotides that can hybridize under stringent conditions with any of six sequences fully defined in the specification that encode the specified CDR, or with sequences having 80% identity after optimal alignment; (3) a vector containing (I); (4) a host cell containing the vector of (3); (5) a non-human transgenic animal containing at least one cell transfected with the vector of (3); (6) producing Ab or its fragments; (7) in vitro diagnosis of diseases induced by over- or under-expression of IGF-1R and or EGFR (epidermal growth factor receptor) by reaction with optionally labeled Ab; and (8) kit for performing method (7). ACTIVITY : Cytostatic; Antipsoriatic. The murine antibody 7C10, specific for IGF-1R, was tested (at 250 Microgram twice a week, intraperitoneally) against MCF-7 breast cancer cells, implanted in nude mice. After 37 days, the mean tumor volume was about 150 mm 3>; compared to about 800 mm 3> for controls and 300 mm 3> for animals treated with 10 Microgram tamoxifen. MECHANISM OF ACTION : Inhibition of signal transduction pathways mediated by IGF-1R, optionally also by epidermal growth factor (EGF) receptor, thus inhibiting growth and/or proliferation of tumor cells, especially where dependent on IGF, EGF, estrogens and/or HER2/neu.