Use of fibronectin fragments for prevention or treatment of angiogenesis-related diseases, e.g. cancer, act by binding fibroblast growth factor-2, also new peptides and related nucleic acids and antibodies

摘要

Use of specific peptides (I) to prepare a composition for prevention or treatment of angiogenesis-related diseases, e.g. cancer, age-related macular degeneration, diabetic retinopathy, psoriasis and rheumatoid arthritis. Use of specific peptides (I) to prepare a composition for prevention or treatment of angiogenesis-related diseases, e.g. cancer, age-related macular degeneration, diabetic retinopathy, psoriasis and rheumatoid arthritis. (I) comprises, or consists of: (a) a sequence that extends to at least amino acids (aa) 275-366 of sequence (S4; 92 aa); 367-455 of sequence (S6; 89 aa) and/or 456-531 of sequence (S8; 76 aa); (b) sequence (S10 ; 545 aa), with only one sequence corresponding to (S10); (c) sequences derived from (a) or (b) by insertion, deletion or mutation of at least one aa; (d) or a sequence at least 85% homologous with (a)-(c), provided (c) and (d) retain ability to bind fibroblast growth factor-2 (FGF-2). All sequences are defined in the specification. Independent claims are also included for the following: (1) use of nucleic acid (II) that encodes (I), or the complement of (II), to produce a composition for prevention or treatment of the specified diseases; (2) pharmaceutical composition that contains (I), (II), a eukaryotic expression vector that contains (II), eukaryotic or prokaryotic cells transformed by (II) or an antiidiotypic antibody (AAb) directed against the paratope of an antibody (Ab) against (I); (3) new peptides (Ia) that comprise, or consist of, aa 270-531 of (S10), but at most comprise a 535 aa sequence (S12), where the sequence adjacent to the ends of (S12) differs from that adjacent to (S12) in human fibronectin, also their derivatives and homologs (as for (I)) that retain ability to bind to FGF-2; (4) new nucleic acid (IIa) that encodes (Ia), and its complement, also sequences that hybridize to (IIa) and its complement; (5) eukaryotic and prokaryotic expression vectors that contain (IIa); (6) eukaryotic and prokaryotic cells transformed by (IIa); (7) antibodies (Ab) raised against (I); and (8) antiidiotypic antibodies (AAb) raised against the paratope of Ab. ACTIVITY : Cytostatic; Ophthalmological; Antidiabetic; Antipsoriatic; Antirheumatic; Antiarthritic. Mice were inoculated with 1 million B16 melanoma cells, then injected with 45 mu g of a plasmid that expressed fibstatin (amino acids 1761-1981 of fibronectin). After 10 days, the mean tumor mass was about 125 mg; compare 240 mg for an untreated control. MECHANISM OF ACTION : (I), also antidiotypic antibodies against the paratope of an anti-(I) antibody, bind to, and block activity of, fibroblast growth factor-2, so have an antiangiogenic effect.