FR2878165A1 - New (mutant) netrin-4, netrin-1, netrin-3, anti-idiotypic netrin-4 antibodies, their Fab fragments or nucleotide sequences useful for preventing or treating tumoral or non-tumoral disorders (of angiogenesis) - Google Patents

Abstract

(Mutant) netrin-4 protein (I) comprising at least 230 amino acids as in SEQ ID. NOs 522 and 524, its fragment, derivative or homologue, is new. (Mutant) netrine-4 protein (I) comprising or contains one of the following sequences; SEQ ID NO. 522 or 524, a fragment of 522/524 with anti-angiogenic activity and/or perictye activation activity, where the fragment comprises between 40 and 450 amino acids, preferably between 40 and 230 amino acids and is represented by SEQ ID NO: 2q, q variant of 187 to 248 or by SEQ ID NO 526 or 528. Also included are the above sequences with substitutions, suppression or addition of one or more amino acids providing that the sequences has anti-angiogenic or perictye activation activity. Active homologues are also included having at least approximiately 50 % sequence identity with the region between amino acids 261 to 515 in SEQ ID NO: 522. Sequence information is not fully defined in the specification. Independent claims are also included for: (1) nucleotide sequence (II) encoding the above proteins of (I); (2) recombinant vector (IV), plasmid, cosmid, phage or DNA virus comprising (II) comprising all necessary elements for expression in a suitable host cell for expression of (I); (3) host cell (IV), chosen from bacteria, viruses, yeast, mushrooms, plants or mammalian cells, transformed by (IV); (4) antibody (V), specific for any of (I); (5) anti-idiotypic antibody (VI) specific for any of (I); ACTIVITY : Cytostatic; Opthalmological; Antiangiogenic; Immunosuppressive; Vasotropic; Hypotensive; Antiarthritic; Cardiant; Anorectic; Cerebroprotective; Dermatological; Antiarteriosclerotic. No biological data is given. MECHANISM OF ACTION : None given.

Description

NEW USES OF NETTRINS

  The subject of the present invention is new uses of netrin, in particular netrin 1, netrin G1, netrin 3 and netrin 4, in particular in the context of the treatment of non-tumor pathologies related to a rarefaction of pericytes.

  Netrin 4 belongs to the family of netrin, which are axon guide molecules. To date, 4 members of this family are known (Netrin 1, G, 3, 4). Netrin 4 is a protein consisting of a C-terminal basic domain interacting with heparin, 3 EGF-like domains and a laminin-like domain (Yurchenko et al., 2004).

  Netrin 1 stimulates attraction when bound to the dcc receptor (or neogenin) and repulsion when bound to dcc receptors and one of the UNC5H family receptors (Livesey et al., 1999; Mehlen et al. 2003, Cooper et al., 1999). In addition, Netrin 1 can bind to the A2 receptor and modify the level of cellular cAMP, the attraction or repulsion being also controlled by the cAMP / cGMP level (Corset et al., 2000).

  Netrin 3 stimulates the attraction of neurons when bound to a dcc or neogenin receptor and induces their repulsion when bound to a receptor of the UNC5H receptor family (Livesey et al., 1999).

  Netrin G represents a family of genes differing from other netrins by the presence of a hydrophobic C-terminal domain binding to glycosylphosphoinositolphosphate (Nakashiba et al., 2002). Their function is still unknown.

  On the other hand, netrin G has been reported to bind neither to dcc nor to UNC5H1, H2 or H3. (Nakashiba et al., 2002) US 2003 / 0207347A1, published November 6, 2003, describes the native netrin 4 and its uses. More particularly, this application describes a polypeptide derived from netrin 4 exhibiting modulation properties of angiogenesis, as well as the use of netrin 4 in a method for modulating vascular development, in particular angiogenesis, and more particularly inhibition of angiogenesis, especially in the context of tumors.

  To date, nothing is known about Netrin 4 receptors or its possible neuronal functions.

  It has recently been published that netrin 1 and netrin 4 inhibit endothelial cell activity via the UNC5H2 receptor (Lu et al., 2004) and inhibit vascularization of the retina.

  The present invention results from the finding by the inventors of the function of activation of pericytes by the binding of nétrines to the receptors UNC5H4 pericytes and smooth muscle cells.

  The present invention relates to the use of: a protein characterized in that it comprises or consists of: * a netrin selected from: Netrin 4, represented by the sequence SEQ ID NO: 2 or SEQ ID NO: 4, netrin 1, represented by the sequence SEQ ID NO: 6 or SEQ ID NO: 8, netrin G1, represented by the sequence SEQ ID NO: 10 or SEQ ID NO: 12, netrin 3, represented by the sequence SEQ ID NO: 14, or * a fragment of one of these proteins, provided that this fragment has pericyte activation activity, said fragment comprising in particular about 40 to about 450 amino acids, and preferably about 40 to about 230 amino acids, and being especially represented by one of the sequences SEQ ID NO: 2n, n ranging from 8 to 254, * any sequence derived from the sequence SEQ ID NO: 2, SEQ ID NO: 6, SEQ ID NO : 10, SEQ ID NO: 14 or a fragment defined above, especially by substitution, deletion or additi one or more amino acids, provided that this derived sequence has a pericyte activation activity, or any sequence homologous to the sequence SEQ ID NO: 2, SEQ ID NO: 6, SEQ ID NO: 10, SEQ ID NO: 14, or a fragment defined above, preferably having a homology of at least about 45% with the region between amino acids at position 13 and 241, or between amino acids at position 242 and 300, or between the amino acids at position 376 and 419 of the sequence SEQ ID NO: 2, provided that this homologous sequence exhibits a pericyte activation activity, or a nucleotide sequence characterized in that it comprises or is constituted by a nucleotide sequence coding: * for one of the netrin as defined above, * or for a fragment of one of the netrin as defined above, * or for a sequence derived from the one of the netrin as defined above s, * for a sequence homologous to one of the netrins as defined above, said nucleotide sequence corresponding in particular to the nucleotide sequence SEQ ID NO: 1 coding for SEQ ID NO: 2, or to the sequence SEQ ID NO: 3 coding for SEQ IL) NO: 4, or the sequence SEQ ID NO: 5 coding for SEQ ID NO: 6, or the sequence SEQ ID NO: 7 coding for SEQ ID NO: 8, or the sequence SEQ ID NO: 9 coding for SEQ ID NO: 10, or the sequence SEQ ID NO: 11 coding for SEQ ID NO: 12, or the sequence SEQ ID NO: 13 coding for SEQ ID NO: 14, or at one of the sequences SEQ ID NO: 2n-1 coding for SEQ ID NO: 2n, n varying from 8 to 254, or an anti-idiotypic antibody of one of the netrins as defined or one of its fragments as defined above, or a derived or homologous sequence as defined above, or an Fab fragment of anti-idiotypic antibodies as defined above, for the preparation of a medicament for the prevention or treatment of non-tumoral pathologies related to, or caused by, rarefaction of pericytes or smooth muscle cells.

  The aforementioned SEQ ID NO: 2n sequences correspond to the protein sequences SEQ ID NO: 16 to SEQ ID NO: 508.

  More specifically, the abovementioned sequences SEQ ID NO: 2n correspond to the following protein sequences: SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO : 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42 , SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO : 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92 , SEQ ID NO: 94, 0017: ON QI? MS 86: ON QI AS 96: ON QI ON 176 ON QI (MS Z6: ON QI & S 06: ON QI & [S 88: ON QI (MS 98: ON IQ? MS 178: ON QI (MS Z8 ON QI? MS 08E: ON QI bS 8L: ON (On 9L ON QI? MS '7L: ON QI on HS ZL: ON QI on HS OL: ON QI on 89: ON IQ (MS 99: ON QI (RIS 179: ONQI? 3S Z9: ONQI? MS 09: ONQI (MS 8S: ON (HAS 9S: ON QI (MS 17S: ON QI (MS ZS: ON QI? MS 'OSE: ON QI 817: ON QI to HS 9t ON CI ajS 17r: ON (H ù s Zi: ON QI? MS 017: ON (I? MS 8: ON (H ¿s 9: ON QI? MS 17: ON QI (MS Z: ON QI âIS 0: ON CI? MS 8Z ON QI (MS 9Z: ON QI? MS 'ta': ON QI (MS ZZ: ON QI? MS OZ: ON QI to '81: ON QI? MS '91: ON QI to '171: ON QI ( MS ZI: ON QI? MS OIE: ON QI? Ms 80: ON QI with 90 ': ON QI with 170: ON QI b IS Z0: ON QI (MS 00 ON QI? MS 86Z: ON QI (MS 96Z: ON QI (MS t76Z: ON QI? MS Z6Z: ON QI? MS 06Z: ON QI? MS 88Z: ON QI aa 98Z: ON QI? MS 178Z: ON QI (MS Z8Z: ON QI? MS 08Z: ON QI? MS 8LZ: ON QI? MS 9LZ: ON QI (MS 17LZ: ON QI (3S ZLZ: ON QI? MS OLZ: ON QI (MAS 89Z ON QI? MS 99Z: ON IQ 179Z: ON QI is Z9Z: ON QI (3S 09Z: ON QI (MS 8SZ: ON QI? MS 9SZ ON QI? MS youZ: ON (H? S ZSZ: ON QI? OSZ: ON QI aaiS 817Z: ON QI ai 91Z: ON QI (MS 17fZ : ON QI ëMS Z1Z: ON QI (MS Ot'Z: ON QI bis 8Z: ON QI? MS 9Z: ON QI? MS 17Z: ON QI ëas ZZ: ON (I low 0Z: ON QI (MS 8ZZ: ON QI (MS 9ZZ: ON QI aaS 17ZZ: ON QI aaS ZZZ: ON QI (MS OZZ: ON QI AqS '8I Z: ON QI ës 9IZ: ON (I down 17l Z: ON (I? MS ZIZ: ON QI bIS 01Z: ON IQ down 80Z: ON QI down 90Z: ON QI? MS t'OZ: ON IQ down ZOZ: ON IQ down OOZ: ON IQ down 861: ON IQ down 961: ON QI low 't6 l: ON QI? MS Z61: ON IQ low 061: ON QI baS 881: ON QI (MS 981: ON IQ low 1781: ON IQ low Z8I: ON IQ low 081: ON IQ low' 8L I: ON QI down '9L1: ON QI? MS' 17L1: ON QI down ZL i: ON QI bs OL I: ON IQ down 891: ON QI (MS 991: ON QI? MS 't791: ON IQ down Z91 : ON QI (MS 091: ON QI ëS 8 IF: ON QI? MS 9SI ON IQ down 17SI: ON QI (MS ZSI: ON QI? MS OS1: ON QI? MS 8171: ON QI down 9171: ON IQ down 17171 : ON IQ down ZVI: ON IQ down 0171: ON QI (MS ON: ON QI down 9Ì: ON III () US 171: ON IQ down ZÌ: ON IQ down 01: ON QI? MS 8Zi: ON IQ down 9Z1: ON QI low t7ZI: ON QI biS ZZI: ON QI (MS OZI ON QI low 811: ON QI low '911: ON QI b S 1711: ON QI (MS' Z11: ON IQ low '011: ON IQ low 801: ON IQ low 901: ON IQ low 1701: ON QI MS 'Z01: ON QI (MS 001: ON IQ (MS 86: ON QI? MS 96: ON QI () US o z oz

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  99 I8L8Z SEQ ID NO: 402, SEQ ID NO: 404, SEQ ID NO: 406, SEQ ID NO: 408, SEQ ID NO: 410, SEQ ID NO: 412, SEQ ID NO: 414, SEQ ID NO: 416, SEQ ID NO: 418, SEQ ID NO: 420, SEQ ID NO: 422, SEQ ID NO: 424, SEQ ID NO: 426, SEQ ID NO: 428, SEQ ID NO: 430, SEQ ID NO: 432, SEQ ID NO: 434, SEQ ID NO: 436, SEQ ID NO: 438, SEQ ID NO: 440, SEQ ID NO: 442, SEQ ID NO: 444, SEQ ID NO: 446, SEQ ID NO: 448, SEQ ID NO: 450, SEQ ID NO: 452, SEQ ID NO: 454, SEQ ID NO: 456, SEQ ID NO: 458, SEQ ID NO: 460, SEQ ID NO: 462, SEQ ID NO: 464, SEQ ID NO: 466, SEQ ID NO: 468, SEQ ID NO: 470, SEQ ID NO: 472, SEQ ID NO: 474, SEQ ID NO: 476, SEQ ID NO: 478, SEQ ID NO: 480, SEQ ID NO: 482, SEQ ID NO: 484, SEQ ID NO: 486, SEQ ID NO: 488, SEQ ID NO: 490, SEQ ID NO: 492, SEQ ID NO: 494, SEQ ID NO: 496, SEQ ID NO: 498, SEQ ID NO: 500, SEQ ID NO: 502, SEQ ID NO: 504, SEQ ID NO: 506 or SEQ ID NO: 508.

  The aforementioned SEQ ID NO: 2n-1 sequences correspond to the nucleotide sequences SEQ ID NO: 15 to SEQ ID NO: 507.

  More specifically, the abovementioned SEQ ID NO: 2n-1 sequences encode the aforementioned protein sequences SEQ ID NO: 2n, and correspond to the following nucleotide sequences: SEQ ID NO: 15 coding for SEQ ID NO: 16, SEQ ID NO: 17 coding for SEQ ID NO: 18, SEQ ID NO: 19 coding for SEQ ID NO: 20, SEQ ID NO: 21 coding for SEQ ID NO: 22, SEQ ID NO: 23 coding for SEQ ID NO: 24, SEQ ID NO : 25 encoding SEQ ID NO: 26, SEQ ID NO: 27 encoding SEQ ID NO: 28, SEQ ID NO: 29 encoding SEQ ID NO: 30, SEQ ID NO: 31 encoding SEQ ID NO: 32, SEQ ID NO: 33 encoding SEQ ID NO: 34, SEQ ID NO: 35 encoding SEQ ID NO: 36, SEQ ID NO: 37 encoding SEQ ID NO: 38, SEQ ID NO: 39 encoding SEQ ID NO: 40 , SEQ ID NO: 41 coding for SEQ ID NO: 42, SEQ ID NO: 43 coding for SEQ ID NO: 44, SEQ ID NO: 45 coding for SEQ ID NO: 46, SEQ ID NO: 47 coding for SEQ ID NO : 48, SEQ ID NO: 49 coding for SEQ ID NO: 50, SEQ ID NO: 51 coding for SEQ ID NO: 52, SEQ ID NO: 53 coding for SEQ ID NO: 54, SEQ ID NO: 55 coding for SEQ ID NO: 56, SEQ ID NO: 57 coding for SEQ ID NO: 58, SEQ ID NO: 59 coding for SEQ ID NO: 60, SEQ ID NO: 61 coding for SEQ ID NO: 62, SEQ ID NO: 63 coding for SEQ ID NO: 64, SEQ ID NO: 65 coding for SEQ ID NO: 66, SEQ ID NO: 67 coding for SEQ ID NO: 68, SEQ ID NO : 69 encoding SEQ ID NO: 70, SEQ ID NO: 71 encoding SEQ ID NO: 72, SEQ ID NO: 73 encoding SEQ ID NO: 74, SEQ ID NO: 75 encoding SEQ ID NO: 76, SEQ ID NO: 77 encoding SEQ ID NO: 78, SEQ ID NO: 79 encoding SEQ ID NO: 80, SEQ ID NO: 81 encoding SEQ ID NO: 82, SEQ ID NO: 83 encoding SEQ ID NO: 84 , SEQ ID NO: 85 encoding SEQ ID NO: 86, SEQ ID NO: 87 encoding SEQ ID NO: 88, SEQ ID NO: 89 encoding SEQ ID NO: 90, SEQ ID NO: 91 encoding SEQ ID NO : 92, SEQ ID NO: 93 encoding SEQ ID NO: 94, SEQ ID NO: 95 encoding SEQ ID NO: 96, SEQ ID NO: 97 encoding SEQ ID NO: 98, SEQ ID NO: 99 encoding SEQ ID NO: 100, SEQ ID NO: 101 coding for SEQ ID NO: 10 2, SEQ ID NO: 103 encoding SEQ ID NO: 104, SEQ ID NO: 105 encoding SEQ ID NO: 106, SEQ ID NO: 107 encoding SEQ ID NO: 108, SEQ ID NO: 109 encoding SEQ ID NO: 110, SEQ ID NO: 111 encoding SEQ ID NO: 112, SEQ ID NO: 113 encoding SEQ ID NO: 114, SEQ ID NO: 115 encoding SEQ ID NO: 116, SEQ ID NO: 117 encoding SEQ ID NO: 118, SEQ ID NO: 119 encoding SEQ ID NO: 120, SEQ ID NO: 121 encoding SEQ ID NO: 122, SEQ ID NO: 123 encoding SEQ ID NO: 124, SEQ ID NO: 125 coding for SEQ ID NO: 126, SEQ ID NO: 127 coding for SEQ ID NO: 128, SEQ ID NO: 129 coding for SEQ ID NO: 130, SEQ ID NO: 131 coding for SEQ ID NO: 132, SEQ ID NO : 133 coding for SEQ ID NO: 134, SEQ ID NO: 135 encoding SEQ ID NO: 136, SEQ ID NO: 137 encoding SEQ ID NO: 138, SEQ ID NO: 139 encoding SEQ ID NO: 140, SEQ ID NO: 141 encoding SEQ ID NO: 142, SEQ ID NO: 143 encoding SEQ ID NO: 144, SEQ ID NO: 145 encoding SEQ ID NO: 146, SEQ ID NO: 147 encoding SEQ ID NO: 148 , SEQ ID N O: 149 coding for SEQ ID NO: 150, SEQ ID NO: 151 coding for SEQ ID NO: 152, SEQ ID NO: 153 coding for SEQ ID NO: 154, SEQ ID NO: 155 coding for SEQ ID NO: 156 , SEQ ID NO: 157 coding for SEQ ID NO: 158, SEQ ID NO: 159 coding for SEQ ID NO: 160, SEQ ID NO: 161 coding for SEQ ID NO: 162, SEQ ID NO: 163 coding for SEQ ID NO : 164, SEQ ID NO: 165 encoding SEQ ID NO: 166, SEQ ID NO: 167 encoding SEQ ID NO: 168, SEQ ID NO: 169 encoding SEQ ID NO: 170, SEQ ID NO: 171 encoding SEQ ID NO: 172, SEQ ID NO: 173 coding for SEQ ID NO: 174, SEQ ID NO: 175 coding for SEQ ID NO: 176, SEQ ID NO: 177 coding for SEQ ID NO: 178, SEQ ID NO: 179 coding for SEQ ID NO: 180, SEQ ID NO: 181 coding for SEQ ID NO: 182, SEQ ID NO: 183 coding for SEQ ID NO: 184, SEQ ID NO: 185 coding for SEQ ID NO: 186, SEQ ID NO: 187 coding for SEQ ID NO: 188, SEQ ID NO: 189 encoding SEQ ID NO: 190, SEQ ID NO: 191 encoding SEQ H) NO: 192, SEQ ID NO: 193 encoding SEQ ID NO: 194, SEQ ID NO: 195 cod ant for SEQ ID NO: 196, SEQ ID NO: 197 encoding SEQ ID NO: 198, SEQ ID NO: 199 encoding SEQ ID NO: 200, SEQ ID NO: 201 encoding SEQ ID NO: 202, SEQ ID NO : 203 coding for SEQ ID NO: 204, SEQ ID NO: 205 coding for SEQ ID NO: 206, SEQ ID NO: 207 coding for SEQ ID NO: 208, SEQ ID NO: 209 encoding SEQ ID NO: 210, SEQ ID NO: 211 coding for SEQ H) NO: 212, SEQ ID NO: 213 coding for SEQ ID NO: 214, SEQ ID NO: 215 coding for SEQ ID NO: 216, SEQ ID NO: 217 coding for SEQ ID NO: 218, SEQ ID NO: 219 coding for SEQ ID NO: 220, SEQ ID NO: 221 coding for SEQ H) NO: 222, SEQ ID NO: 223 coding for SEQ ID NO: 224, SEQ ID NO: 225 coding for SEQ ID NO: 226, SEQ ID NO: 227 coding for SEQ ID NO: 228, SEQ ID NO: 229 coding for SEQ ID NO: 230, SEQ ID NO: 231 coding for SEQ H) NO: 232, SEQ ID NO: 233 coding for SEQ ID NO: 234, SEQ ID NO: 235 coding for SEQ ID NO: 236, SEQ ID NO: 237 coding for SEQ ID NO: 238, SEQ ID NO: 239 coding for SEQ ID NO: 240, SEQ ID NO : 241 coding for SE Q ID NO: 242, SEQ ID NO: 243 coding for SEQ ID NO: 244, SEQ ID NO: 245 coding for SEQ ID NO: 246, SEQ ID NO: 247 coding for SEQ ID NO: 248, SEQ ID NO: 249 coding for SEQ ID NO: 250, SEQ ID NO: 251 coding for SEQ ID NO: 252, SEQ ID NO: 253 coding for SEQ ID NO: 254, SEQ ID NO: 255 coding for SEQ ID NO: 256, SEQ ID NO : 257 coding for SEQ ID NO: 258, SEQ ID NO: 259 coding for SEQ ID NO: 260, SEQ ID NO: 261 coding for SEQ ID NO: 262, SEQ ID NO: 263 coding for SEQ ID NO: 264, SEQ ID NO: 265 encoding SEQ ID NO: 266, SEQ ID NO: 267 encoding SEQ ID NO: 268, SEQ ID NO: 269 encoding SEQ ID NO: 270, SEQ ID NO: 271 encoding SEQ ID NO: 272 , SEQ ID NO: 273 coding for SEQ ID NO: 274, SEQ ID NO: 275 coding for SEQ H) NO: 276, SEQ ID NO: 277 coding for SEQ ID NO: 278, SEQ ID NO: 279 coding for SEQ ID NO: 280, SEQ ID NO: 281 coding for SEQ ID NO: 282, SEQ ID NO: 283 coding for SEQ ID NO: 284, SEQ ID NO: 285 coding for SEQ ID NO: 286, SEQ ID NO: 287 coding for SEQ ID NO: 28 8, SEQ ID NO: 289 coding for SEQ ID NO: 290, SEQ ID NO: 291 coding for SEQ ID NO: 292, SEQ ID NO: 293 coding for SEQ ID NO: 294, SEQ ID NO: 295 coding for SEQ ID NO: 296, SEQ ID NO: 297 coding for SEQ ID NO: 298, SEQ ID NO: 299 coding for SEQ ID NO: 300, SEQ ID NO: 301 coding for SEQ ID NO: 302, SEQ ID NO: 303 coding for SEQ ID NO: 304, SEQ ID NO: 305 coding for SEQ ID NO: 306, SEQ ID NO: 307 coding for SEQ ID NO: 308, SEQ ID NO: 309 coding for SEQ ID NO: 310, SEQ ID NO: 311 coding for SEQ ID NO: 312, SEQ ID NO: 313 coding for SEQ ID NO: 314, SEQ ID NO: 315 coding for SEQ II) NO: 316, SEQ ID NO: 317 coding for SEQ ID NO: 318, SEQ ID NO: 319 coding for SEQ ID NO: 320, SEQ ID NO: 321 coding for SEQ ID NO: 322, SEQ ID NO: 323 coding for SEQ ID NO: 324, SEQ ID NO: 325 coding for SEQ II) NO: 326 , SEQ ID NO: 327 coding for SEQ ID NO: 328, SEQ ID NO: 329 coding for SEQ ID NO: 330, SEQ ID NO: 331 coding for SEQ ID NO: 332, SEQ ID NO: 333 coding for SEQ ID NO : 334, SEQ ID NO: 335 coding for SEQ ID NO: 336, SEQ ID NO: 337 coding for SEQ ID NO: 338, SEQ ID NO: 339 coding for SEQ ID NO: 340, SEQ ID NO: 341 coding for SEQ ID NO: 342, SEQ ID NO: 343 coding for SEQ ID NO: 344, SEQ ID NO: 345 coding for SEQ II) NO: 346, SEQ ID NO: 347 coding for SEQ ID NO: 348, SEQ ID NO: 349 coding for SEQ ID NO : 350, SEQ ID NO: 351 coding for SEQ ID NO: 352, SEQ ID NO: 353 coding for SEQ ID NO: 354, SEQ ID NO: 355 coding for SEQ II) NO: 356, SEQ ID NO: 357 coding for SEQ ID NO: 358, SEQ ID NO: 359 coding for SEQ ID NO: 360, SEQ ID NO: 361 coding for SEQ ID NO: 362, SEQ ID NO: 363 coding for SEQ ID NO: 364, SEQ ID NO: 365 coding for SEQ II) NO: 366, SEQ ID NO: 367 coding for SEQ ID NO: 368, SEQ ID NO: 369 coding for SEQ ID NO: 370, SEQ ID NO: 371 coding for SEQ ID NO: 372, SEQ ID NO: 373 coding for SEQ ID NO: 374, SEQ ID NO: 375 coding for SEQ 11) NO: 376, SEQ ID NO: 377 coding for SEQ ID NO: 378, SEQ ID NO: 379 coding for SEQ ID NO: 380 , SEQ ID NO: 38 1 coding for SEQ ID NO: 382, SEQ ID NO: 383 coding for SEQ ID NO: 384, SEQ ID NO: 385 coding for SEQ II) NO: 386, SEQ ID NO: 387 coding for SEQ ID NO: 388, SEQ ID NO: 389 encoding SEQ ID NO: 390, SEQ ID NO: 391 encoding SEQ ID NO: 392, SEQ ID NO: 393 encoding SEQ ID NO: 394, SEQ ID NO: 395 encoding SEQ ID NO: 396 , SEQ ID NO: 397 coding for SEQ ID NO: 398, SEQ ID NO: 399 coding for SEQ ID NO: 400, SEQ ID NO: 401 coding for SEQ ID NO: 402, SEQ ID NO: 403 coding for SEQ ID NO : 404, SEQ ID NO: 405 encoding SEQ ID NO: 406, SEQ ID NO: 407 encoding SEQ ID NO: 408, SEQ ID NO: 409 encoding SEQ ID NO: 410, SEQ ID NO: 411 encoding SEQ ID NO: 412, SEQ ID NO: 413 coding for SEQ ID NO: 414, SEQ ID NO: 415 coding for SEQ ID NO: 416, SEQ ID NO: 417 coding for SEQ ID NO: 418, SEQ ID NO: 419 coding for SEQ ID NO: 420, SEQ ID NO: 421 coding for SEQ ID NO: 422, SEQ ID NO: 423 coding for SEQ ID NO: 424, SEQ ID NO: 425 coding for SEQ ID NO: 426, SEQ ID NO: 427 coding p SEQ ID NO: 428, SEQ ID NO: 429 encoding SEQ ID NO: 430, SEQ ID NO: 431 encoding SEQ ID NO: 432, SEQ ID NO: 433 encoding SEQ ID NO: 434, SEQ ID NO: 435 coding for SEQ ID NO: 436, SEQ ID NO: 437 encoding SEQ ID NO: 438, SEQ ID NO: 439 encoding SEQ ID NO: 440, SEQ ID NO: 441 encoding SEQ ID NO: 442, SEQ ID NO: 443 coding for SEQ ID NO: 444, SEQ ID NO: 445 coding for SEQ H) NO: 446, SEQ ID NO: 447 coding for SEQ ID NO: 448, SEQ ID NO: 449 coding for SEQ ID NO: 450 , SEQ ID NO: 451 coding for SEQ ID NO: 452, SEQ ID NO: 453 coding for SEQ ID NO: 454, SEQ ID NO: 455 coding for SEQ ID NO: 456, SEQ ID NO: 457 coding for SEQ ID NO : 458, SEQ ID NO: 459 encoding SEQ ID NO: 460, SEQ ID NO: 461 encoding SEQ ID NO: 462, SEQ ID NO: 463 encoding SEQ ID NO: 464, SEQ ID NO: 465 encoding SEQ ID NO: 466, SEQ ID NO: 467 coding for SEQ ID NO: 468, SEQ ID NO: 469 coding for SEQ ID NO: 470, SEQ ID NO: 471 coding for SEQ ID NO: 472, SEQ ID NO: 473 coding for SEQ ID NO: 474, SEQ ID NO: 475 coding for SEQ ID NO: 476, SEQ ID NO: 477 coding for SEQ ID NO: 478, SEQ ID NO: 479 coding for SEQ ID NO: 480, SEQ ID NO: 481 coding for SEQ ID NO: 482, SEQ ID NO: 483 coding for SEQ ID NO: 484, SEQ ID NO: 485 coding for SEQ ID NO: 486, SEQ ID NO: 487 coding for SEQ ID NO: 488, SEQ ID NO: 489 coding for SEQ ID NO: 490, SEQ ID NO: 491 coding for SEQ ID NO: 492, SEQ ID NO: 493 coding for SEQ ID NO: 494, SEQ ID NO: 495 coding for SEQ ID NO: 496, SEQ ID NO : 497 coding for SEQ ID NO: 498, SEQ ID NO: 499 coding for SEQ ID NO: 500, SEQ ID NO: 501 coding for SEQ ID NO: 502, SEQ ID NO: 503 coding for SEQ ID NO: 504, SEQ ID NO: 505 encoding SEQ ID NO: 506 or SEQ ID NO: 507 encoding SEQ ID NO: 508.

  The sequence SEQ ID NO: 2 corresponds to the netrin 4 human protein encoded by the nucleotide sequence SEQ ID NO: 1, and the sequence SEQ ID NO: 4 corresponds to the aforementioned netrin 4 human protein without the signal peptide, encoded by the sequence nucleotide SEQ ID NO: 3. The sequence SEQ ID NO: 2 comprises 628 amino acids and the sequence SEQ ID NO: 4 comprises 609 amino acids and corresponds to a fragment of the sequence SEQ ID NO: 2 ranging from residue 20 to residue 628 .

  The sequence SEQ ID NO: 6 corresponds to the netrin 1 human protein encoded by the nucleotide sequence SEQ ID NO: 5, and the sequence SEQ ID NO: 8 corresponds to the above-mentioned human netrin 1 protein without the signal peptide encoded by the sequence. nucleotide SEQ ID NO: 7. The sequence SEQ ID NO: 6 comprises 604 amino acids and the sequence SEQ ID NO: 8 comprises 580 amino acids and corresponds to a fragment of the sequence SEQ ID NO: 6 ranging from residue 25 to residue 604 .

  The sequence SEQ ID NO: 10 corresponds to the human netrin G1 protein encoded by the nucleotide sequence SEQ ID NO: 9, and the sequence SEQ ID NO: 12 corresponds to the aforementioned human netrin G1 protein without the signal peptide, encoded by the sequence nucleotide SEQ ID NO: 11. The sequence SEQ ID NO: 10 comprises 438 amino acids and the sequence SEQ ID NO: 12 comprises 410 amino acids and corresponds to a fragment of the sequence SEQ ID NO: 10 from residue 29 to residue 438 .

  The sequence SEQ ID NO: 14 corresponds to the human netrin 3 protein encoded by the nucleotide sequence SEQ ID NO: 13. The sequence SEQ ID NO: 14 comprises 580 amino acids.

  The sequence SEQ ID NO: 382 corresponds to a mutated netrin 4 human protein, encoded by the nucleotide sequence SEQ ID NO: 381, and the sequence SEQ ID NO: 384 corresponds to the abovementioned mutated protein without the signal peptide, coded by the sequence nucleotide SEQ ID NO: 383. The sequence SEQ ID NO: 382 comprises 628 amino acids and the sequence SEQ ID NO: 384 comprises 609 amino acids and corresponds to a fragment of the sequence SEQ ID NO: 382 from residue 20 to residue 628 .

  The sequence SEQ ID NO: 16 corresponds to a laminin-type fragment (extracellular matrix protein binding to certain integrins) of the human netrin 4 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 15. This fragment comprises 260 amino acids and corresponds to the fragment of the netrin 4 protein ranging from residue 1 to residue 260 of the sequence SEQ ID NO: 2.

  The sequence SEQ ID NO: 18 corresponds to an EGF (EGF factor factor repetition domain) fragment of the human netrin 4 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 17. This fragment comprises 255 amino acids and corresponds to to the fragment of netrin 4 protein from residue 261 to residue 515 of the sequence SEQ ID NO: 2.

  The sequence SEQ ID NO: 20 corresponds to the heparin-binding fragment of the human netrin 4 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 19. This fragment comprises 113 amino acids and corresponds to the fragment of the protein. netrin 4 from residue 516 to residue 628 of sequence SEQ ID NO: 2.

  The sequence SEQ ID NO: 22 is a fragment corresponding to the netrin 4 human protein deleted of the sequence SEQ ID NO: 20, said fragment being encoded by the nucleotide sequence SEQ ID NO: 21. This fragment comprises 515 amino acids and corresponds to fragment of the netrin 4 protein from residue 1 to residue 515 of the sequence SEQ ID NO: 2.

  The sequence SEQ ID NO: 34 is a laminin type fragment of the human netrin 4 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 33. This fragment comprises 229 amino acids and corresponds to the fragment of the netrin 4 protein from residue 32 to residue 260 of the sequence SEQ ID NO: 2.

  The sequence SEQ ID NO: 28 is an EGF-like fragment of the human netrin 4 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 27. This fragment comprises 60 amino acids and corresponds to the fragment of the netrin 4 protein from residue 261 to residue 320 of the sequence SEQ ID NO: 2.

  The sequence SEQ ID NO: 30 is an EGF-like fragment of the human netrin 4 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 29. This fragment comprises 56 amino acids and corresponds to the fragment of the netrin 4 protein from residue 332 to residue 387 of the sequence SEQ ID NO: 2.

  The sequence SEQ ID NO: 32 is an EGF-like fragment of the human netrin 4 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 31. This fragment comprises 52 amino acids and corresponds to the fragment of the netrin 4 protein from residue 394 to residue 445 of the sequence SEQ ID NO: 2.

  The fragments of the netrin 4 protein corresponding to the protein sequences SEQ ID NO: 24 to SEQ ID NO: 152, as well as the corresponding nucleotide sequences SEQ ID NO: 23 to SEQ ID NO: 151 are grouped in the following table: Protein sequence Nucleotide sequence Positions of the fragment with respect to the sequence SEQ ID NO: 2 SEQ ID NO: 24 SEQ ID NO: 23 32-515 SEQ ID NO: 26 SEQ ID NO: 25 32-628 SEQ ID NO: 28 SEQ ID NO: 27 261-320 SEQ ID NO: 30 SEQ ID NO: 29 332-387 SEQ ID NO: 32 SEQ ID NO: 31 394-445 SEQ ID NO: 34 SEQ ID NO: 33 32-260 SEQ ID NO: 36 SEQ ID NO: 35 1-260 + 516-628 SEQ ID NO: 38 SEQ ID NO: 37 261-628 SEQ ID NO: 40 SEQ ID NO: 39 1-320 SEQ ID NO: 42 SEQ ID NO: 41 1- 260 + 332-387 SEQ ID NO: 44 SEQ ID NO: 43 1-260 + 394-445 SEQ ID NO: 46 SEQ ID NO: 45 32-320 SEQ ID NO: 48 SEQ ID NO: 47 32-260 + 332-387 SEQ ID NO: 50 SEQ ID NO: 49 32-260 + 394-445 SEQ ID NO: 52 SEQ ID NO: 51 261-320 + 332-387 SEQ ID NO: 54 SEQ ID NO: 53 332-387 + 394- 445 SEQ ID NO: 56 SEQ ID NO: 55 261-320 + 394-445 SEQ ID NO: 58 SEQ ID NO: 57 261-320 + 332-387 + 394-445 SEQ ID NO: 60 SEQ ID NO: 59 1-320 + 332-387 SEQ ID NO: 62 SEQ ID NO: 61 1-260 + 332-387 + 394-445 SEQ ID NO: 64 SEQ ID NO: 63 1-320 + 394- 445 SEQ ID NO: 66 SEQ ID NO: 65 32- 320 + 332-387 SEQ ID NO: 68 SEQ ID NO: 67 32-260 + 332-387 + 394-445 SEQ ID NO: 70 SEQ ID NO: 69 32-320 + 394- 445 SEQ ID NO: 72 SEQ ID NO: 71 1-320 + 332-387 + 394-445 SEQ ID NO: 74 SEQ ID NO: 73 32-320 + 332-387 + 394-445

_

  SEQ ID NO: 76 SEQ ID NO: 75 261-320 + 516-628 SEQ ID NO: 78 SEQ ID NO: 77 332-387 + 516-628 SEQ ID NO: 80 SEQ ID NO: 79 _ 394-445 + 516 -628 SEQ ID NO: 82 SEQ ID NO: 81 32-260 + 516-628 SEQ ID NO: 84 SEQ ID NO: 83 _ 32320 + 516-628 SEQ ID NO: 86 SEQ ID NO: 85 _ 32-260 + 332-387 + 516-628 SEQ ID NO: 88 SEQ ID NO: 87 32-260 + 394-445 + 516-628 SEQ ID NO: 90 SEQ ID NO: _ 1-320 + 516-628 SEQ ID NO: 92 SEQ ID NO: 91 1-260 + 332-387 + 516-628

_

  SEQ ID NO: 94 SEQ ID NO: 93 1-260 + 394-445 + 516-628

_

  SEQ ID NO: 96 SEQ ID NO: 95 _ 261-320 + 332-387 + 516-628 SEQ ID NO: 98 SEQ ID NO: 97 261-320 + 394-445 + 516-628

_

  SEQ ID NO: 100 SEQ ID NO: 99 332-387 + 394-445 + 516-628 SEQ ID NO: 102 SEQ ID NO: 101 261-320 + 332-387 + 394-445 + 516-628 SEQ ID NO: SEQ ID NO: 103 1-320 332-387 + 516-628 SEQ ID NO: 106 SEQ ID NO: 105 1-260 + 332-387 + 394-445 + 516-628 SEQ ID NO: 108 SEQ ID NO: 1-320 394-445 + 516-628 SEQ ID NO: 110 SEQ ID NO: 109 32-320 + 332-387 + 516-628 SEQ ID NO .: 112 SEQ ID NO: 111 32-260 + 332-387 + 394 -445 + 516-628 SEQ ID NO: 114 SEQ ID NO: 113 32-320 + 394-445 + 516-628 SEQ ID NO: 116 SEQ ID NO: 115 1-320 + 332-387 + 394-445 + 516 -628 SEQ ID NO: 118 SEQ ID NO: 117 32-320 + 332-387 + 394-445 + 516-628 SEQ ID NO: 120 SEQ ID NO: 119 20-260 SEQ ID NO: 122 SEQ ID NO: 121 20-516 SEQ ID NO: 124 SEQ ID NO: 123 20-260 + 516-628 SEQ ID NO: 126 SEQ ID NO: 125 20-320 SEQ ID NO: 128 SEQ ID NO: 127 20-260 + 332-387 SEQ ID NO: 130 SEQ ID NO: 129 20-260 + 394-445 SEQ ID NO: 132 SEQ ID NO: 131 20-320 + 332-387 SEQ ID NO: 134 SEQ ID NO: 133 20-260 + 332- 387 + 394-445 SEQ ID NO: 136 SEQ ID NO: 1 20-320 + 394-445 SEQ ID NO: 138 SEQ ID NO: 137 20-320 + 332-387 + 394-445 SEQ ID NO: 140 SEQ ID NO: 139 20-320 + 516-628 SEQ ID NO: SEQ ID NO: 141 20-260 + 332-387 + 516-628 SEQ ID NO: 144 SEQ ID NO: 143 20-260 + 394-445 + 516- 628 SEQ ID NO: 146 SEQ ID NO: 145 20- 320 + 332-387 + 516-628 SEQ ID NO: 148 SEQ ID NO: 147 20-260 + 332-387 + 394-445 + 516-628 SEQ ID NO: 150 SEQ ID NO: 149 20-320 + 394- 445 + 516-628 SEQ ID NO: 152 SEQ ID NO: 151 20-320 + 332-387 + 394-445 + 516-628 The sequence SEQ ID NO: 154 corresponds to a laminin type fragment (extracellular matrix protein binding to certain integrins) of the human netrin 1 protein, said fragment being: encoded by the nucleotide sequence SEQ ID NO: 153. This fragment comprises 283 amino acids and corresponds to the fragment of the netrin 1 protein ranging from residue 1 to residue 283 of the sequence SEQ ID NO: 6.

  The sequence SEQ ID NO: 156 corresponds to an EGF (EGF factor repetition domain) fragment of the human netrin 1 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO 155. This fragment comprises 204 amino acids and corresponds to the fragment of netrin 1 protein from residue 284 to residue 487 of the sequence SEQ ID NO: 6.

  The sequence SEQ ID NO: 158 corresponds to the heparin-binding fragment of the human netrin 1 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 157. This fragment comprises 117 amino acids and corresponds to the fragment of the protein. netrin 1 from residue 488 to residue 604 of sequence SEQ ID NO: 6.

  The sequence SEQ ID NO: 160 is a fragment corresponding to the human netrin 1 protein deleted of the sequence SEQ ID NO: 158, said fragment being encoded by the nucleotide sequence SEQ ID NO: 159. This fragment comprises 487 amino acids and corresponds to fragment of the netrin 1 protein from residue 1 to residue 487 of the sequence SEQ ID NO: 6.

  The sequence SEQ ID NO: 168 is a laminin type fragment of the human netrin 1 protein, said fragment being: encoded by the nucleotide sequence SEQ ID NO: 167. This fragment comprises 235 amino acids and corresponds to the fragment of the netrin 1 protein from residue 49 to residue 283 of the sequence SEQ ID NO: 6.

  The sequence SEQ ID NO: 162 is an EGF-like fragment of the human netrin 1 protein, said fragment being. encoded by the nucleotide sequence SEQ ID NO: 161. This fragment comprises 48 amino acids and corresponds to the fragment of the netrin 1 protein from the residue 284 to the residue 331 of the sequence SEQ ID NO: 6.

  The sequence SEQ ID NO: 164 is an EGF-like fragment of the human netrin 1 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 163. This fragment comprises 56 amino acids and corresponds to the fragment of the netrin 1 protein from residue 341 to residue 396 of the sequence SEQ ID NO: 6.

  The sequence SEQ ID NO: 166 is an EGF-like fragment of the human netrin 1 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 165. This fragment comprises 48 amino acids and corresponds to the fragment of the netrin 1 protein from residue 403 to residue 450 of the sequence SEQ ID NO: 6.

  The fragments of the netrin 1 protein corresponding to the protein sequences SEQ ID NO: 170 to SEQ ID NO: 290, as well as the corresponding nucleotide sequences SEQ ID NO: 169 to SEQ II) NO: 289 are grouped in the following table: Protein Nucleotide sequence Positions of the fragment with respect to the sequence SEQ ID NO: 6 SEQ ID NO: 170 SEQ ID NO: 169 1-283 + 488-604 SEQ ID NO: 172 SEQ ID NO: 171 284-604 SEQ ID NO: 174 SEQ ID NO: 173 49-487 SEQ ID NO: 176 SEQ ID NO: 175 49-604 SEQ ID NO: 178 SEQ ID NO: 177 1-331 96-117 + 8Z-SZ S9Z: ON CU HSHS 99Z: ON CU q S-9 Z Z Z Z Z 17 17 17 17 17 17 17 17 170 170 170 170 170 CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU CU 8SZ ON â 1709-8817 + OS17-Ò17 + 96-117 + 1-617 SSZ: ONCU i 9SZ: INGO S 1709-8817 + OSt7-017 + 96-117 + I -I SZ ON CU q 17SZ ON GlâqS 1709-8817 + OSt7-017 + 1 -617 I SZ: ON CU MS ZSZ: ON CU 3S 1709-8817 + OS17-017 + 96-117 + 8Z-617 6172 ON UT US OST: 1709-8817 + 96-117 + 1 -617 L17Z: ON 817Z: ON CU 1709-8817 + OS17-017 + I-1 S17Z: ON UI-HS 917Z ON GI 1709-8817 8817 + OSt7-017 + 96-117 + 8Z-i 17Z ON CU to M 1717Z: ON UI to 1709-8817 + 96-117 + 1-1 I17Z: ON to Z17Z: ON Cil aM 1709-8817 + 0Sb-0i7 + 96-117 + 1-t78Z 6Z: ON m bIS O 'Z: ON to as 1709-8817 + OSt-017 + 96-It7 LZ: ON TI to 8Z: ON GUHS 1709-8817 + OS17-017 + I - 178Z SZ: ON UT aaS 9Z ON GU? MS 1709-8817 + 96-11 + 1 -18Z Z ON CU to 172: ON to s 1709-881 + OSt-017 + 8Z-IIZ ON CU SIZE ZZ: ON CU M 1709-8817 + 96-I17 + 8Z-I 6ZZ: CU CU CU â â â 0ZZZZZ U U U U U 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 170 1709-8817 + 617 SZZ: ON CU 9ZZ: ON CU 1709-8817 + 96-117 + 8Z-617 ZZ ON 17ZZ: ON UI 1709-8817 + 1 -617 1 ZZ: ON CU ZZZ: ON UI 1709- 8817 + 8Z-617 61Z: ON UI AqS 0ZZ: ON UI a3S 1709-881 + OS17-: 017 LIZ: ON 8IZ: ONCU 1709-8817 + 96-117 SIZ: ONGIaS 91Z: UNIDO 1709-8817 + 1- 178Z ÌZ: ONCU qS 171Z: ONUIâ S OS17-017 + 96-117 + 1-617 1IZ: ON UI J ZTZ: ON UI J OS17-017 + 96-117-1-1-I 60Z: ONUIâS 01Z: ONCU âaS () St0I7 + 1 -617 LOZ: ON UI HS 80Z: ON UI AqS OS17-017 + 96-117 + 8Z-617 SOZ: ON CU TO HS 90Z: ON CU TO 96-117 + 1 -617 ÒZ: ON Gl to 170Z: ON UI 0S17-017 + 1 -I 10Z: ON CU ZOZ: ON cn low OS17-017 + 96-it - ± 8Z-1 661: ON Cll to 00Z: ON UI low 96-117 + 1-1 L61: ON m 861: ON Cs OS17-Òt + 96-117 + I-178Z S61: ON CU 969: ON UI OS17-017 + 1 -t8Z 61: ON UT aaS 1761: ON UI aaS OS17-017 + 96 -117 161: ON UI low Z61: ON UI to 96-117 + 1 -t8Z 681: ON CU AqS 061: ON UT baS OS17-017 + 8Z-617 L81 ON CU aa 881: ON CU 96-117 + 8Z -617 S81 ON CU 981: ON CU 1 -617 81: On Low 1781: ON UI OS17-017 + 8Z-I 181: ON UI to Z81: ON UI to HS 96-117 + 8Z-i 6L1: ON IU 081: ON UI low Si 99 I8L8Z SEQ ID NO: 268 SEQ ID NO: 267 25-283 + 403-450 SEQ ID NO: 270 SEQ ID NO: 269 25-331 + 341-396 SEQ ID NO: 272 SEQ ID NO: 271-25-2 83 + 341-396 + 403-450 SEQ ID NO: 274 SEQ ID NO: 273 25-331 + 403-450 SEQ ID NO: 276 SEQ ID NO: 275 25-331 341-396 + 403-450 SEQ ID NO: 278 SEQ ID NO: 277 25-331 + 488-604 SEQ ID NO: 280 SEQ ID NO: 279 25-283 341-396 + 488-604 SEQ ID NO: 282 SEQ ID NO: 281 25- 283 403-450 + 488-604 SEQ ID NO: 284 SEQ ID NO: 283 25-331 341-396 + 488-604 SEQ ID NO: 286 SEQ ID NO: 285 25-283 + 341-396 + 403-450 + 488-604 SEQ ID NO: 288 SEQ ID NO: 287 25-331 + 403-450 + 488-604 SEQ ID NO: 290 _ SEQ ID NO: 289 25-331 + 341-396 + 403-450 + 488-604 The sequence SEQ ID NO : 292 corresponds to a laminin type fragment (extracellular matrix protein binding to certain integrins) of the human netrin G1 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 291. This fragment comprises 295 amino acids and corresponds to to the fragment of the netrin protein G1 from residue 1 to residue 295 of the sequence SEQ ID NO: 10.

  The sequence SEQ ID NO: 294 corresponds to an EGF (EGF factor repetition domain) fragment of the human netrin G1 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 293. This fragment comprises 143 amino acids and corresponds to to the fragment of the netrin protein G1 from residue 296 to residue 438 of the sequence SEQ ID NO: 10.

  The sequence SEQ ID NO: 296 is a laminin type fragment of the human netrin G1 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 295. This fragment comprises 225 amino acids and corresponds to the fragment of the netrin G1 protein ranging from from residue 71 to residue 295 of the sequence SEQ ID NO: 10.

  The sequence SEQ ID NO: 298 is an EGF-like fragment of the human netrin G1 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 297. This fragment comprises 47 amino acids and corresponds to the fragment of the netrinin Gi protein from residue 296 to residue 342 of the sequence SEQ ID NO: 10.

  The sequence SEQ ID NO: 300 is an EGF-like fragment of the human netrin G1 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 299. This fragment comprises 37 amino acids and corresponds to the fragment of the netrin G1 protein ranging from from residue 373 to residue 409 of the sequence SEQ ID NO: 10.

  The fragments of the netrin G 1 protein corresponding to the protein sequences SEQ ID NO: 302 to SEQ ID NO: 324, as well as the corresponding nucleotide sequences SEQ ID NO: 301 to SEQ II) NO: 323 are grouped in the following table: Protein sequence Nucleotide sequence Positions of the fragment with respect to the sequence SEQ ID NO: 10 SEQ ID NO: 302 SEQ ID NO: 301 1-342 SEQ ID NO: 304 SEQ ID NO: 303 1295 + 373-409 SEQ ID NO: 306 SEQ ID NO: 305 1-342 + 373-409 SEQ ID NO: 308 SEQ ID NO: 307 71-438 SEQ ID NO: 310 SEQ ID NO: 309 71-342 SEQ ID NO: 312 SEQ ID NO: 311 71 -295 + 373-409 SEQ ID NO: 314 SEQ ID NO: 313 296-342 + 373-409 SEQ ID NO: 316 SEQ ID NO: 315 71-342 + 373-409 SEQ ID NO: 318 SEQ ID NO: 317 29-295 SEQ ID NO: 320 SEQ ID NO: 319 29-342 SEQ ID NO: 322 SEQ ID NO: 321 29-295 + 373-409 SEQ ID NO: 324 SEQ ID NO: 323 29-342 + 373-409 The sequence SEQ ID NO: 326 corresponds to a laminin type fragment (protein of the extracellular matrix binding to cerium). integrins) of the human netrin 3 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 325. This fragment comprises 253 amino acids and corresponds to the fragment of the netrin 3 protein from residue 1 to residue 253 of the SEQ sequence ID NO: 14

  The sequence SEQ ID NO: 328 is a laminin type fragment of the human netrin 3 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 327. This fragment comprises 220 amino acids and corresponds to the fragment of the netrin 3 protein from residue 34 to residue 253 of the sequence SEQ ID NO: 14.

  The sequence SEQ ID NO: 330 corresponds to an EGF (EGF factor repetition domain) fragment of the human netrin 3 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 329. This fragment comprises 180 amino acids and corresponds to to the fragment of the netrin 3 protein from residue 254 to residue 433 of the sequence SEQ ID NO: 14.

  The sequence SEQ ID NO: 332 is an EGF-like fragment of the human netrin 3 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 331. This fragment comprises 46 amino acids and corresponds to the fragment of the netrin 3 protein from residue 254 to residue 299 of the sequence SEQ ID NO: 14.

  The sequence SEQ ID NO: 334 is an EGF-like fragment of the human netrin 3 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 333. This fragment comprises 50 amino acids and corresponds to the fragment of the netrin 3 protein from residue 373 to residue 422 of the sequence SEQ ID NO: 14.

  The sequence SEQ ID NO: 336 corresponds to the heparin-binding fragment of the human netrin 3 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 335. This fragment comprises 148 amino acids and corresponds to the fragment of the protein. Netrin 3 from residue 433 to residue 580 of sequence SEQ ID NO: 14.

  The fragments of the netrin 3 protein corresponding to the protein sequences SEQ ID NO: 338 to SEQ ID NO: 380, as well as the corresponding nucleotide sequences SEQ ID NO: 337 to SEQ II) NO: 379 are grouped in the following table: Protein Nucleotide sequence Positions of the fragment with respect to the sequence SEQ ID NO: 14 SEQ ID NO: 338 SEQ ID NO: 337 1-422 SEQ ID NO: 340 SEQ ID NO: 339 254433 SEQ ID NO: 342 SEQ ID NO: 341 1-253 + 433-580 SEQ ID NO: 344 SEQ ID NO: 343 1-299 SEQ ID NO: 346 SEQ ID NO: 345 1-253 + 373-422 SEQ ID NO: 348 SEQ ID NO: 347 1-299 + 373-422 SEQ ID NO: 350 SEQ ID NO: 349 254-299 + 433-580 SEQ ID NO: 352 SEQ ID NO: 351 373-422 + 433-580 SEQ ID NO: 354 SEQ ID NO: 353 254- 299 + 373-422 SEQ ID NO: 356 SEQ ID NO: 355 254-299 + 373-422 + 433-580 SEQ ID NO: 358 SEQ ID NO: 357 1-299 + 433-580 SEQ ID NO: 360 SEQ ID NO: 359 1-253 + 373-422 + 433-580 SEQ ID NO: 362 SEQ ID NO: 361 1-299 + 373-422 + 433-580 SEQ ID NO: 364 SEQ ID NO: 363 34-4 33 SEQ ID NO: 366 SEQ ID NO: 365 34-253 + 433-580 SEQ ID NO: 368 SEQ ID NO: 367 34-299 SEQ ID NO: 370 SEQ ID NO: 369 34-253 + 373-422 SEQ ID NO: 372 SEQ ID NO: 371 34-580 SEQ ID NO: 374 SEQ ID NO: 373 34-299 + 373-422 SEQ ID NO: 376 SEQ ID NO: 375 34-299 + 433-580 SEQ ID NO: 378 SEQ ID NO: 377 34-253 + 373-422 + 433-580 SEQ ID NO: 380 SEQ ID NO: 379 34-299 + 373-422 + 433-580 The mutated Netrin 4, represented by the sequence SEQ ID NO: 382, corresponds to the netrin 4 protein represented by SEQ ID NO: 2 having the following 9 point mutations: replacement of cysteine at position 13 with arginine, replacement of lysine at position 68 with threonine, replacement of serine in position 183 by a proline, replacement of histidine at position 205 with a tyrosine, replacement of cysteine at position 234 with a tyrosine, replacement of alanine at position 331 with asparagine, replacement of cysteine at position 332 with arginine , replacement of asparagine at position 353 with serine, replacement of asparagine at position 515 with lysine.

  The sequence SEQ ID NO: 386 corresponds to a laminin-like fragment (extracellular matrix protein binding to certain integrins) of the mutated human netrin 4 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 385. This fragment comprises 260 amino acids and corresponds to the fragment of the netrin 4 protein from residue 1 to residue 260 of the sequence SEQ ID NO: 382.

  The sequence SEQ ID NO: 388 corresponds to an EGF (EGF factor repetition domain) fragment of the mutated netrin 4 human protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 387. This fragment comprises 255 amino acids and corresponds to the fragment of the netrin 4 protein from residue 261 to residue 515 of the sequence SEQ ID NO: 382.

  The sequence SEQ ID NO: 390 is a fragment corresponding to the mutated human netrin 4 protein deleted of the sequence SEQ ID NO: 20, said fragment being encoded by the nucleotide sequence SEQ ID NO: 389. This fragment comprises 515 amino acids and corresponds to to the netrin 4 protein fragment from residue 1 to residue 515 of sequence SEQ ID NO: 382.

  The sequence SEQ ID NO: 398 is a laminin-like fragment of the mutated human netrin 4 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 397. This fragment comprises 229 amino acids and corresponds to the fragment of the netrin protein. 4 from residue 32 to residue 260 of the sequence SEQ ID NO: 382.

  The sequence SEQ ID NO: 396 is an EGF-like fragment of the mutated human netrin 4 protein, said fragment being encoded by the nucleotide sequence SEQ ID NO: 395. This fragment comprises 56 amino acids and corresponds to the fragment of the netrin 4 protein. ranging from residue 332 to residue 387 of sequence SEQ ID NO: 382.

  The fragments of the mutated netrin 4 protein corresponding to the protein sequences SEQ ID NO: 392 to SEQ ID NO: 508, as well as the corresponding nucleotide sequences SEQ ID NO: 391 to SEQ ID NO: 507 are grouped in the following table: Protein Nucleotide sequence fragment positions with respect to the sequence SEQ ID NO: 382 SEQ ID NO: 392 SEQ ID NO: 391 32-515 SEQ ID NO: 394 SEQ ID NO: 393 32628 SEQ ID NO: 396 SEQ ID NO: 395 332-387 SEQ ID NO: 398 SEQ ID NO: 397 32-260 SEQ ID NO: 400 SEQ ID NO: 399 1-260 + 516-628 SEQ ID NO: 402 SEQ ID NO: 401 261-628 SEQ ID NO: 404 SEQ ID NO: 403 1-320 SEQ ID NO: 406 SEQ ID NO: 405 1-260 + 332-387 SEQ ID NO: 408 SEQ ID NO: 407 1-260 + 394-445 SEQ ID NO: 410 SEQ ID NO: 409 32-320 SEQ ID NO: 412 SEQ ID NO: 411 32-260 + 332-387 SEQ ID NO: 414 SEQ ID NO: 413 32-260 + 394-445 SEQ ID NO: 416 SEQ ID NO: 415 261-320 + 332-387 SEQ ID NO: 418 SEQ ID NO: 417 332-387 + 394-445 SEQ ID NO: 420 SEQ ID NO: 419 261-320 + 332-387 + 394-445 SEQ ID NO: 422 SEQ ID NO: 421 1-320 + 332-387 SEQ ID NO: 424 SEQ ID NO: 423 1260 332-387 + 394-445 SEQ ID NO: 426 SEQ ID NO: 425 1 -320 + 394-445 SEQ ID NO: 428 SEQ ID NO: 427 32-320 + 332-387 SEQ ID NO: 430 SEQ ID NO: 429 32-260 + 332-387 + 394-445 SEQ ID NO: 432 SEQ ID NO: 431 32-320 + 394-445 SEQ ID NO: 434 SEQ ID NO: 433 1-320 + 332-387 + 394-445 SEQ ID NO: 436 SEQ ID NO: 435 32-320 + 332-387 + 394-445 SEQ ID NO: 438 SEQ ID NO: 437 332387 + 516-628 SEQ ID NO: 440 SEQ ID NO: 439 32-260 + 516-628 SEQ ID NO: 442 SEQ ID NO: 441 32-320 + 516 -628 SEQ ID NO: 444 SEQ ID NO: 443 132-260 + 332-387 + 516-628 SEQ ID NO: 446 SEQ ID NO: 445 32-260 + 394-445 + 516628 SEQ ID NO: 448 SEQ ID NO : 447 1-320 + 516-628 SEQ ID NO .: 450 SEQ ID NO: 449 1-260 + 332-387 + 516-628 SEQ ID NO: 452 SEQ ID NO: 451 1-260 + 394-445 + 516- 628 SEQ ID NO: 454 SEQ ID NO: 453 261-320 + 332-387 + 516628 SEQ ID NO: 456 SEQ ID NO: 455 332-387 + 394-445 + 516-628 SEQ ID NO: 458 SEQ ID NO: 457 261-320 + 332-387 + 394 -445 + 516-628 SEQ ID NO: 460 SEQ ID NO: 459 1-320 + 332-387 + 516-628 SEQ ID NO: 462 SEQ ID NO: 461 1260 + 332-387 + 394-445 + 516-628 SEQ ID NO: 464 SEQ ID NO: 463 1-320 + 394-445 + 516-628 SEQ ID NO: 466 SEQ ID NO: 465 32-320 + 332-387 + 516628 SEQ ID NO: 468 SEQ ID NO: 467 32-260 + 332-387 + 394-445 + 516-628 SEQ ID NO: 470 SEQ ID NO: 469 32-320 + 394-445 + 516-628 SEQ ID NO: 472 SEQ ID NO: 471 1-320 + 332-387 + 394-445 + 516-628 SEQ ID NO: 474 SEQ ID NO: 473 32-320 + 332-387 + 394-445 + 516-628 SEQ ID NO: 476 SEQ ID NO: 475 20-260 SEQ ID NO: 478 SEQ ID NO: 477 20-516 SEQ ID NO: 480 SEQ ID NO: 479 20-260 + 516-628 SEQ ID NO: 482 SEQ ID NO: 481 20-320 SEQ ID NO: 484 SEQ ID NO : 483 20-260 + 332-387 SEQ ID NO: 486 SEQ ID NO: 485 20-260 + 394-445 SEQ ID NO: 488 SEQ ID NO: 487 20--320 + 332-387 SEQ ID NO: 490 SEQ ID NO: 489 20-260-h 332-387 + 394-445 SEQ ID NO: 492 SEQ ID NO: 491 20.-320 + 394-445 SEQ ID NO: 494 SEQ ID NO: 493 20-320 + 332- 387 + 394-445 SEQ ID NO: 496 SEQ ID NO: 495 20- 320 + 516-628 SEQ ID NO: 498 SEQ ID NO: 497 20-260 + 332-387 + 516-628 SEQ ID NO: 500 SEQ ID NO: 499 20-260 + 394-445 + 516-628 SEQ ID NO : 502 SEQ ID NO: 501 20-320 + 332-387 + 516-628 SEQ ID NO: 504 SEQ ID NO .: 503 20-260 + 332.-387 + 394-445 + 516-628 SEQ ID NO: 506 SEQ ID NO: 505 20-320 + 394-445 + 516-628 SEQ ID NO: 508 SEQ ID NO: 507 20-320 + 332.-387 + 394-445 + 516-628 Activation activity of pericytes is checked in particular by the proliferation and migration tests as described below: - after and in the experimental part. The present invention also relates to the use of: a protein as defined above, or a nucleotide sequence as defined above, or an anti-idiotypic antibody as defined above, for the preparation of a medicament for the prevention or treatment of non-tumoral pathologies related to or caused by a rarefaction of pericytes or smooth muscle cells, and possibly by activation of endothelial cell proliferation.

  The activation activity of the endothelial cells is verified in particular by the proliferation tests as described below.

  Angiogenesis inhibitory activity is also referred to as antiangiogenic activity. This activity can for example be demonstrated in vitro by demonstrating the inhibition of both the multiplication, migration and differentiation of endothelial cells by the peptide sequences of the invention. Measurement of the inhibition of endothelial cell multiplication can be achieved by culturing endothelial cells in the presence of the peptide sequence whose activity is to be evaluated. Measurement of inhibition of endothelial cell migration can be accomplished by wounding an endothelial cell mat and then incubating the cells in the presence of the peptide sequence to be tested. The number of cells that migrated to the wound is then measured.

  Measurement of the inhibition of differentiation (tubulogenesis) of endothelial cells can be performed by measuring the length of tubules formed by endothelial cells cultured on gel in the presence of the peptide sequence to be tested.

  Among the conventional models for measuring angiogenesis, mention may be made of local delivery models such as: the subcutaneous injection of Matrigel (Becton Dickinson) impregnated with the compound of the invention (Inoki et al., 2002), or the depositing on the chorioaloidoidal chicken membrane of an implant containing a compound of the invention (Celerier et al., 2002).

  According to an advantageous embodiment, the use according to the present invention is characterized in that the non-tumoral pathologies related to or caused by a rarefaction of pericytes or smooth muscle cells, and requiring activation of the proliferation or migration of pericytes or smooth muscle cells, are chosen from: age-related macular degeneration, diabetic retinopathies, neovascular glaucoma, rheumatoid arthritis, psoriasis, in particular psoriatic arthritis, angiomas, atherosclerosis, obesity, intestinal malformations, Crohn's disease, vascular dementia, vascular subcorticals of which Cadasil is a

example,

  Alzheimer's disease, degenerative bone diseases and fractures, and aneurysms and vascular dissections.

  According to an advantageous embodiment, the use according to the present invention is characterized in that the non-tumoral pathologies related to or caused by a rarefaction of pericytes or smooth muscle cells, and requiring activation of the proliferation or migration of pericytes or smooth muscle cells, are chosen from: diabetic retinopathies, intestinal malformations, Crohn's disease, atherosclerosis, obesity, vascular dementia, such as Alzheimer's disease, degenerative bone diseases and fractures, and aneurysms and vascular dissections.

  The present invention also relates to the use as defined above, characterized in that the activation activity of the proliferation or migration of pericytes or smooth muscle cells is measured according to the proliferation or migration test, and in that this activation activity corresponds to at least 120% of the cells obtained in the absence of the protein, or the nucleotide sequence or the anti-idiotypic antibody as defined above.

  This property can be used to expand smooth muscle cells or pericytes from any progenitor cell or stem cell collection to perform cell therapies.

  Measurement of the activation of pericyte or smooth muscle cell migration can be accomplished by "weaving" on a carpet of cells and then incubating the cells in the presence of the protein, or nucleotide sequence, or antiidiotypic antibody to be tested. The number of cells that migrated to the wound is then measured.

  The measurement of the activation of the proliferation of pericytes or smooth muscle cells can be carried out by placing the pericytes or smooth muscle cells in a suitable culture medium, in particular in DMEM medium containing no serum, and then measuring the total number of cells.

  The present invention also relates to the use as defined above, characterized in that the inhibition activity of the. Atheroma plaque formation is measured according to the abovementioned proliferation or migration test, and in that this inhibition activity corresponds to a percentage inhibition of between 20% and 100% of the atheroma plaques obtained in the atherosclerotic plaque. absence of the protein, or the nucleotide sequence or the anti-idiotypic antibody as defined above.

  The anti-atheromatous activity is measured by the test as described in Arnal et al. (2003).

  According to an advantageous embodiment, the present invention relates to the use as defined above, netrin protein 4, represented by the sequence SEQ ID NO: 2 or SEQ ID NO: 4, as active substance.

  The present invention also relates to the use as defined above of the netrin 4 protein, represented by the sequence SEQ ID NO: 2 or SEQ ID NO: 4, for the preparation of a medicinal product which can be administered with reasonable from about 0.1 to about 20 mg / kg / day, especially intravenously, subcutaneously, systemically, intravitreously, locally by infiltration or via an eye drop, possibly associated with electropermination.

  Netrin 4 protein can also be delivered by an injection of plasmid encoding the netrin 4 protein of interest.

  Alternatively, any of the netins of the invention or a fragment thereof may be delivered by any intravascular device method (stents) after attachment of the protein or fragment to said device.

  The present invention also relates to the use as defined above, of the fragment of the netrin 4 protein represented by SEQ ID NO: 20, or of a protein or a peptide containing the sequence SEQ ID NO: 20, d a gene coding for this fragment, or for this protein or peptide containing this fragment.

  The present invention also relates to the use as defined above, of anti-idiotypic antibodies of a netrin, in particular netrin 4 protein, represented by the sequence SEQ ID NO: 2 or SEQ ID NO: 4, said antiidiotypic antibodies being characterized in that they recognize the UNC5H4 receptor on the surface of pericytes or muscle cells: risses.

  The inventors have demonstrated that only the UNC5H4 receptor is associated with the stimulatory action of muscle cells and pericytes of Netrin 1, 3, 4 and G1.

  According to an advantageous embodiment, the present invention relates to the use as defined above of anti-idiotypic antibodies of a netrin, in particular netrin 4 protein, represented by the sequence SEQ ID NO: 2 or SEQ ID NO: 4, recognizing the UNC5H4 receptor on the surface of pericytes or smooth muscle cells, for the preparation of a medicament for the prevention or treatment of the following pathologies: age-related macular degeneration, diabetic retinopathies, glaucoma neovascular, rheumatoid arthritis, psoriasis, especially psoriatic arthritis, angiomas, atherosclerosis, obesity, intestinal malformations, Crohn's disease, vascular dementia, vascular subcorticals of which Cadasil is an example, Alzheimer's disease, degenerative bone diseases and fractures, and aneurysms and vascular dissections.

  The present invention also relates to the use of the UNC5H4 receptor on the surface of pericytes or smooth muscle cells, or pericytes or smooth muscle cells carrying these receptors, for the implementation of a method for screening compounds that promote proliferation. or the migration of pericytes or smooth muscle cells.

  The present invention relates to a method for screening compounds which promote the proliferation or migration of pericytes or smooth muscle cells, characterized in that it comprises the following steps: the measurement of the inhibition of the binding of netrin 4 to its UNC5H4 receptor, or inhibition of mitogenic, chemotactic, antiapoptotic or differentiation activity of netrin or other netrin-like factor on smooth or pericyte muscle cells, and measurement of the loss of inhibition of the mitogenic or chemotactic or anti-apoptotic activity or differentiation of netrin or any other netrin-like factor on smooth or pericyte muscle cells by addition of an antibody neutralizing the UNC5H4 receptor.

  The tests used in the context of this screening method are the tests as described above for proliferation or migration.

  The present invention relates to a method for screening compounds that modulate the binding between the UNC5H4 receptor and netrin 4 represented by the sequence SEQ ID NO: 2 or SEQ ID NO: 4, characterized in that it comprises the following steps: bringing said modulator compound into contact with the UNC5H4 receptor and netrin 4, and measuring the specific binding level between the UNC5H4 receptor and netrin 4, a difference in said level in the presence of said compound relative to the normal level in the absence of said compound being an indication of the property of said compound to modulate the binding between the UNC5H4 receptor and netrin 4.

  The screening test is carried out as follows: Goat immunoglobulins directed against Fc domains of human IgG are incubated on microtiter plates (0.1-20 g / ml in 50 mM carbonate buffer pH 9.6) . After saturation of the nonspecific sites by a solution of serum albumin diluted to 5 mg / ml in the same buffer, the proteins containing the extracellular domains of the UNC5H4 receptor fused to a Fc sequence of human IgG are immobilized on the microtiter plates (incubation at a concentration of between 1 and 1000 ng / ml). The compounds are added serially diluted in PBS buffer containing 0.05% Tween 20 and 10-500 μg Netrin 1, 3, 4 or G labeled by any suitable method (radioactive iodine, biotin, fluorochrome). After rinsing, the amount of netrin bound to the receptor is revealed either by adding an appropriate concentration of anti-netrin antibody coupled to peroxidase, either by measuring radioactivity, or by adding peroxidase-coupled avidin, or by fluorescence measurement. The peroxidase is then revealed by a colorimetric reaction. In all cases, the amount of test compound is measured by its ability to inhibit the amount of netrin fixed.

  The present invention also relates to netrin fragments, characterized in that they comprise or consist of one of the following sequences: * one of the sequences SEQ ID NO: 2p, p varying from 14 to 190, or * any a sequence derived from one of the abovementioned sequences, in particular by substitution, deletion or addition of one or more amino acids, provided that this derived sequence has pericyte activation activity, or any homologous sequence of one or more amino acids, above-mentioned sequences, preferably having an identity of at least about 50% with the region between the amino acids at position 261 and 515 of SEQ ID NO: 2, provided that this homologous sequence exhibits pericyte activation activity .

  The abovementioned SEQ ID NO: 2p sequences correspond to the protein sequences SEQ ID NO: 28 to SEQ ID NO: 380 and are new fragments of netrin 4, netrin 1, netrin G1 and netrin 3; they also have anti-angiogenic activity.

  The present invention also relates to a protein, characterized in that it comprises or consists of one of the following sequences: * the sequence SEQ ID NO: 382 or SEQ ID NO: 384, or * a fragment of one of these proteins, provided that this fragment has a pericyte activation activity, said fragment comprising in particular about 40 to about 450 amino acids, and preferably from about 40 to about 230 amino acids, and being especially represented by one sequences SEQ ID NO: 2i, i varying from 193 to 254, any sequence derived from one of the abovementioned sequences, in particular by substitution, deletion or addition of one or more amino acids, provided that this derived sequence has a pericyte activation activity, or any sequence homologous to: one of the abovementioned sequences, preferably having an identity of at least about 50% with the region between the amino acids in position 261 and 515 of SEQ ID NO: 2, provided that this homologous sequence exhibits pericyte activation activity.

  The aforementioned protein SEQ ID NO: 382 is a new protein corresponding to the mutated netrin 4 protein and the above-mentioned protein SEQ ID NO: 384 corresponds to the protein SEQ ID NO: 382 without signal peptide. These two proteins also have antiangiogenic activity.

  The aforementioned fragments, corresponding to the protein sequences SEQ ID NO: 386 to SEQ ID NO: 508, are new fragments corresponding to fragments of the above mutated netrin 4; they also have anti-angiogenic activity.

  The abovementioned SEQ ID NO: 2i sequences correspond to the following protein sequences: SEQ ID NO: 386, SEQ ID NO: 388, SEQ ID NO: 390, SEQ ID NO: 392, SEQ ID NO: 394, SEQ ID NO: 396, SEQ ID NO: 398, SEQ ID NO: 400, SEQ ID NO: 402, SEQ ID NO: 404, SEQ ID NO: 406, SEQ ID NO: 408, SEQ ID NO: 410, SEQ ID NO: 412, SEQ ID NO: 414, SEQ ID NO: 416, SEQ ID NO: 418, SEQ ID NO: 420, SEQ ID NO: 422, SEQ ID NO: 424, SEQ ID NO: 426, SEQ ID NO: 428, SEQ ID NO: 430, SEQ ID NO: 432, SEQ ID NO: 434, SEQ ID NO: 436, SEQ ID NO: 438, SEQ ID NO: 440, SEQ ID NO: 442, SEQ ID NO: 444, SEQ ID NO: 446, SEQ ID NO: 448, SEQ ID NO: 450, SEQ ID NO: 452, SEQ ID NO: 454, SEQ ID NO: 456, SEQ ID NO: 458, SEQ ID NO: 460, SEQ ID NO: 462, SEQ ID NO: 464, SEQ ID NO: 466, SEQ ID NO: 468, SEQ ID NO: 470, SEQ ID NO: 472, SEQ ID NO: 474, SEQ ID NO: 476, SEQ ID NO: 478, SEQ ID NO: 480, SEQ ID NO: 482, SEQ ID NO: 484, SEQ ID NO: 486, SEQ ID NO: 488, SEQ ID NO: 490, SEQ ID NO: 492, SEQ ID NO: 494, SEQ ID NO: 496, SEQ ID NO: 498, SEQ ID NO: 500, SEQ ID NO: 502, SEQ ID NO: 504, SEQ ID NO: 506 or SEQ ID NO: 508.

  The present invention also relates to a nucleotide sequence encoding a protein as defined above.

  A preferred nucleotide sequence according to the invention is a nucleotide sequence characterized in that it comprises or consists of: one of the nucleotide sequences SEQ ID NO: 2p-1 coding for SEQ ID NO: 2p, p varying from 14 to 190, or any nucleotide sequence derived, by degeneracy of the genetic code, from one of the abovementioned nucleotide sequences, and coding for a protein represented by one of the sequences SEQ ID NO: 2p, p ranging from 14 to 190, or any nucleotide sequence derived, in particular by substitution, deletion or addition of one or more nucleotides, of one of the abovementioned nucleotide sequences coding for a protein derived from SEQ ID NO: 2p, p ranging from 14 to 190, as defined above. above, or any nucleotide sequence homologous to one of the abovementioned nucleotide sequences, preferably having an identity of at least about 50%, with one of the SE sequences Q ID NO: 2p-1 encoding a homologous protein of SEQ ID NO: 2p, as defined above, or any nucleotide sequence complementary to the abovementioned sequences, or any nucleotide sequence capable of hybridizing under stringent conditions with the sequence complementary to one of the above-mentioned sequences.

  A preferred nucleotide sequence according to the invention is a nucleotide sequence characterized in that it comprises or consists of: the nucleotide sequence SEQ ID NO: 381 coding for SEQ ID NO: 382, or the nucleotide sequence SEQ ID NO: 383 coding for SEQ ID NO: 384, a fragment of one of these nucleotide sequences, and in particular represented by one of the sequences SEQ ID NO: 2i-1, i ranging from 193 to 254, or any nucleotide sequence derived, by degeneracy the genetic code, of one of the aforementioned nucleotide sequences, and coding for a protein represented by one of the sequences SEQ ID NO: 2i, i varying from 193 to 254, or any nucleotide sequence derived, in particular by substitution, deletion or addition of one or more nucleotides of one of the abovementioned nucleotide sequences coding for a protein derived from SEQ ID NO: 2i, i ranging from 193 to 254, as defined above; s, or any homologous nucleotide sequence of one of the abovementioned nucleotide sequences, preferably having an identity of at least about 50%, with one of the sequences SEQ ID NO: 2i-1 coding for a homologous protein of SEQ ID NO: 2i, as defined above, or any nucleotide sequence complementary to the aforementioned sequences, or any nucleotide sequence capable of hybridizing under stringent conditions with the sequence complementary to one of the abovementioned sequences.

  The expression "hybridize under stringent conditions" corresponds in particular to a hybridization buffer such as 0.5X SSC, at a hybridization temperature of 60 C, as well as to a washing medium such as 0.1X SSC added of 1% SDS and at a washing temperature of 50 C.

  The abovementioned SEQ ID NO: 2i-1 sequences encode the aforementioned protein sequences SEQ ID NO: 2i, and correspond to the following nucleotide sequences: SEQ ID NO: 385 coding for SEQ ID NO: 386, SEQ ID NO: 387 coding for SEQ ID NO: 388, SEQ ID NO: 389 coding for SEQ ID NO: 390, SEQ ID NO: 391 coding for SEQ II) NO: 392, SEQ ID NO: 393 coding for SEQ ID NO: 394, SEQ ID NO: 395 coding for SEQ ID NO: 396, SEQ ID NO: 397 coding for SEQ ID NO: 398, SEQ ID NO: 399 coding for SEQ ID NO: 400, SEQ ID NO: 401 coding for SEQ II) NO: 402, SEQ ID NO: 403 coding for SEQ ID NO: 404, SEQ ID NO: 405 coding for SEQ ID NO: 406, SEQ ID NO: 407 coding for SEQ ID NO: 408, SEQ ID NO: 409 coding for SEQ ID NO: 410, SEQ ID NO: 411 coding for SEQ II) NO: 412, SEQ ID NO: 413 coding for SEQ ID NO: 414, SEQ ID NO: 415 coding for SEQ ID NO: 416, SEQ ID NO: 417 coding for SEQ ID NO : 418, SEQ ID NO: 419 coding for SEQ ID NO: 420, SEQ ID NO: 421 coding for SEQ II) NO: 422, SEQ ID NO: 423 encoding SEQ ID NO: 424, SEQ ID NO: 425 encoding SEQ ID NO: 426, SEQ ID NO: 427 encoding SEQ ID NO: 428, SEQ ID NO: 429 encoding SEQ ID NO: 430 , SEQ ID NO: 431 coding for SEQ ID NO: 432, SEQ ID NO: 433 coding for SEQ ID NO: 434, SEQ ID NO: 435 coding for SEQ ID NO: 436, SEQ ID NO: 437 coding for SEQ ID NO : 438, SEQ ID NO: 439 coding for SEQ ID NO: 440, SEQ ID NO: 441 coding for SEQ II) NO: 442, SEQ ID NO: 443 coding for SEQ ID NO: 444, SEQ ID NO: 445 coding for SEQ ID NO: 446, SEQ ID NO: 447 coding for SEQ ID NO: 448, SEQ ID NO: 449 coding for SEQ ID NO: 450, SEQ ID NO: 451 coding for SEQ ID NO: 452, SEQ ID NO: 453 coding for SEQ ID NO: 454, SEQ ID NO: 455 coding for SEQ ID NO: 456, SEQ ID NO: 457 coding for SEQ ID NO: 458, SEQ ID NO: 459 coding for SEQ ID NO: 460, SEQ ID NO : 461 coding for SEQ II) NO: 462, SEQ ID NO: 463 encoding SEQ ID NO: 464, SEQ ID NO: 465 encoding SEQ ID NO: 466, SEQ ID NO: 467 encoding SEQ ID NO: 468, SEQ ID NO: 46 9 coding for SEQ ID NO: 470, SEQ ID NO: 471 coding for SEQ II) NO: 472, SEQ ID NO: 473 coding for SEQ ID NO: 474, SEQ ID NO: 475 coding for SEQ ID NO: 476, SEQ ID NO: 477 coding for SEQ ID NO: 478, SEQ ID NO: 479 coding for SEQ ID NO: 480, SEQ ID NO: 481 coding for SEQ ID NO: 482, SEQ ID NO: 483 coding for SEQ ID NO: 484 , SEQ ID NO: 485 coding for SEQ ID NO: 486, SEQ ID NO: 487 coding for SEQ ID NO: 488, SEQ ID NO: 489 coding for SEQ ID NO: 490, SEQ ID NO: 491 coding for SEQ ID NO : 492, SEQ ID NO: 493 coding for SEQ ID NO: 494, SEQ ID NO: 495 coding for SEQ ID NO: 496, SEQ ID NO: 497 coding for SEQ ID NO: 498, SEQ ID NO: 499 coding for SEQ ID NO: 500, SEQ ID NO: 501 coding for SEQ H) NO: 502, SEQ ID NO: 503 coding for SEQ ID NO: 504, SEQ ID NO: 505 coding for SEQ ID NO: 506 or SEQ ID NO: 507 coding for SEQ ID NO: 508.

  The present invention also relates to a recombinant vector, in particular plasmid, cosmid, phage or virus DNA, containing a nucleotide sequence as defined above.

  The present invention also relates to a recombinant vector as defined above, containing the elements necessary for the expression in a host cell of the polypeptides encoded by the nucleic acids as defined above, inserted in said vector.

  The present invention relates to a host cell, chosen in particular from bacteria, viruses, yeasts, fungi, plants or mammalian cells, said host cell being transformed, in particular using a recombinant vector as defined above.

  The present invention also relates to an antibody characterized in that it is specifically directed against a netrin fragment as defined above.

  The present invention also relates to an antiidiotypic monoclonal antibody, specific for the above-mentioned UNC5H4 receptor, directed against an antibody as defined above. This antiidiotypic antibody is a mime of the netrin fragment used to prepare the antibody against which this anti-idiotypic antibody is directed. Thus, this anti-idiotypic antibody may be an agonist or antagonist of UNC5H4. If it is an agonist of UNC5H4, it stimulates the functions of smooth muscle cells without inhibiting or stimulating netrin functions on endothelial cells. If it is an antagonist of UNC5H4, it inhibits the stimulatory action of netrin on the function of smooth muscle cells without inhibiting or stimulating netrin functions on endothelial cells.

  The present invention also relates to an Fab fragment of an anti-idiotypic monoclonal antibody as defined above, in particular having an antagonistic activity.

  Proteins Protein sequence Nuclein 4 nucleotide sequence (with signal peptide) (1-628) SEQ ID NO: 2 SEQ ID NO: 1 Netrin 4 (without signal peptide) (20-628) SEQ ID NO: 4 SEQ ID NO: 3 Netrin 1 (with signal peptide) (1-604) SEQ ID NO: 6 SEQ ID NO: 5 Netrin 1 (without signal peptide) (25-604) SEQ ID NO: 8 SEQ ID NO: 7 Netrin G (with signal peptide) (1-530) SEQ ID NO: 10 SEQ ID NO: 9 Netrin G (without signal peptide) (18-530) SEQ ID NO: 12 SEQ ID NO: 11 Netrin 3 (1-580) SEQ ID NO: 14 SEQ ID NO: 13 Mutated Netrin 4 (with signal peptide) (1-628) SEQ ID NO: 382 SEQ ID NO: 381 Mutated Netrin 4 (without signal peptide) (20-628) SEQ ID NO: 384 SEQ ID NO: 383 Netrin Fragments 4 Protein Sequence Nucleotide Sequence 1 (1-260) SEQ ID NO: 16 SEQ ID NO: 15 2 (261-515) SEQ ID NO: 18 SEQ ID NO: 17 3 (516-628) SEQ ID NO: SEQ ID NO: 19 1 + 2 (1-515) SEQ ID NO: 22 SEQ ID NO: 21a + 2 (32-515) SEQ ID NO: 24 SEQ ID NO: 23a + 2 + 3 (32-) 628) SEQ ID NO: 26 SEQ ID NO: 25 2a (261-320) SEQ ID NO: SEQ ID NO: 27 2b (332-387) SEQ ID NO: 30 SEQ ID NO: 29 EL ON IQ PL: On HSH (Stit-i6 + L8-Z + OZ-I9Z + 09Z-Z) 3Z + qZ + ' Z + tj IL: ON ZL: ON Cff iS (S6t'-66 + L8- Z + OZ-I9Z + 09Z-I) 3Z + qZ + 'Z + i 69: ON CHO S OL: ON (HâIS (St ## EQU1 ## where: ## STR1 ##: ## STR2 ## ## EQU1 ## ## STR2 ## ## STR2 ## ## STR2 ## I) 3Z + EZ + T 19: ON alas Z9: ON a? MS (S17t'-t'6 + L8-Z + 092-1) 3Z + qZ + I 6S ON C11 to S 09 ON to S (L8 -Z + OZ-19Z + 092-1) qZ + 'Z + I LS ON (II to 8S: OII (1T to TT (St'P-f76 + L8-Z + OR-19Z) 3Z + qZ + uZ SS: ON ( ## EQU1 ## (HS-FR6 + OZ-19Z) 3Z-FEZ S ON (HASHS bS: ON (H2S (Sf711-1'6 + L8-Z) 3Z + qZ I ON CE-ZS: ON CRYSTAL (L8-Z + OZ- [9Z) qZ + uz 617: ON UT ON OS: On (Sf7f9-'6i + 09Z-Z) 3Z + 1T Lt: ON (Hsi 817 : ON QI b S (L8-Z + 09Z-Z) qZ + EI Sb: ON (H HS HS 917: ON (H S S (OZ-19Z + 0922) '2 +' T 17: ON â 1717 ON CU S (Sfrt'-1; + 092-1) 3Z + I It: ON CEI Zb: ON al bs (L8-Z + 09Z-I) qZ + I 6: ON QI? Ms 017: ON 01 to (02-192 + 09Z-I) TZ + IL: ON 01 to HS 8: ON (HI) (8Z9-19Z) + ZS: ON G1 to 9: ON CEE (8Z9-91 + 09Z-D + T: ON (H) [S t: ON IQ ## STR00006 ## 2b + 3 (332-387 + 516-628) SEQ ID NO: 78 SEQ ID NO: 77 2c + 3 (394-445 + 516-628) SEQ ID NO: 80 SEQ ID NO: 79 + 3f32-260 + 516 -628) SEQ ID NO: 82 SEQ ID NO: 81a + 2a + 3 (32-260 + 261-320 + 516-628) SEQ ID NO: 84 SEQ ID NO: 83a + 2b + 3 (32-260 + 332-387 + 516628) SEQ ID NO: 86 SEQ ID NO: 85a + 2c + 3 (32-260 + 394-445 + 516-628) SEQ ID NO: 88 SEQ ID NO: 87 1 + 2a + 3 (1-260 + 261-320 + 516-628) SEQ ID NO: 90 SEQ ID NO: 89 1 + 2b + 3 (1-260 + 332-387 + 516-628) SEQ ID NO: 92 SEQ ID NO: 91 1 + 2c + 3 (1-260 + 394-445 + 516-628) SEQ ID NO: 94 SEQ ID NO: 93 2a + 2b + 3 (261-320 + 332-387 + 516-628) SEQ ID NO : 96 SEQ ID NO: 95 2a + 2c + 3 (261320 + 394-445 + 516-628) SEQ ID N O: 98 SEQ ID NO: 97 2b + 2c + 3 (332-387 + 394-445 + 516-628) SEQ ID NO: 100 SEQ ID NO: 99 2a + 2b + 2c + 3 (261-320 + 332387 + 394-445 + 516-628) SEQ ID NO: 102 SEQ ID NO: 101 1+ 2a + 2b + 3 (1-260 + 261-320 + 332-387 + 516-628) SEQ ID NO: 104 SEQ ID NO : 103 1 + 2b + 2c + 3 (1260 + 332-387 + 394-445 + 516-628) SEQ ID NO: 106 SEQ ID NO: 105 1 + 2a + 2c + 3 (1-260 + 261-320 + 394 -445 + 516-628) SEQ ID NO: 108 SEQ ID NO: 107a + 2a + 2b + 3 (32-260 + 261-320 + 332-387 + 516-628) SEQ ID NO: 110 SEQ ID NO: 109 the + 2b + 2c + 3 (32-260 + 332-387 + 394-445 + 516-628) SEQ ID NO: 112 SEQ ID NO: 111 the + 2a + 2c + 3 (32-260 + 261-320 + 394-445 + 516-628) SEQ ID NO: 114 SEQ ID NO: 113 1 + 2a + 2b + 2c + 3 (1-260 + 261-320 + 332-387 + 394-445 + 516-628) SEQ ID NO: 116 SEQ ID NO: 115a + 2a + 2b + 2c + 3 (32-260 + 261-320 + 332-387 + 394-445 + 516-628) SEQ ID NO: 118 SEQ ID NO: 117 1 without signal peptide (20-260) SEQ ID NO: 120 SEQ ID NO: 119 1 + 2 without signal peptide (20516) SEQ ID NO: 122 SEQ ID NO: 121 1 + 3 without signal peptide (20-260 + 516628) SEQ ID NO SEQ ID NO: 123 1 + 2a without signal peptide (20-260 + 261320) SEQ ID NO: 126 SEQ ID NO: 125 1 + 2b without signal peptide (20-260 + 332387) SEQ ID NO: 128 SEQ ID NO: 127 1 + 2c without signal peptide (20-260 + 394445) SEQ ID NO: 130 SEQ ID NO: 129 1 + 2a + 2b without signal peptide (20-260 + 261-320 + 332-387) SEQ ID NO : 132 SEQ ID NO: 131 1 + 2b + 2c without signal peptide (20-260 + 332-387 + 394-445) SEQ ID NO: 134 SEQ ID NO: 133 1 + 2a + 2c without signal peptide (20-260 + 261-320 + 394-445) SEQ ID NO: 136 SEQ ID NO: 135 1 + 2a + 2b + 2c without signal peptide (20-260 + 261-320 + 332-387 + 394-445) SEQ ID NO: SEQ ID NO: 137 1 + 2a + 3 without signal peptide (20-260 + 261-320 + 516-628) SEQ ID NO: 140 SEQ ID NO: 139 1 + 2b + 3 without signal peptide (20-260 + 332-387 + 516-628) SEQ ID NO: 142 SEQ ID NO: 141 1 + 2c + 3 without signal peptide (20-260 + 394-445 + 516-628) SEQ ID m.) .144 SEQ ID NO: 143 1 + 2a + 2b + 3 without signal peptide (20-260 + 261-320 + 332-387 + 516-628) SEQ ID NO: 146 SEQ ID NO: 145 1 + 2b + 2c + 3 without signal peptide (20 -260 + 332-387 + 394-445 + 516-628) SEQ ID NO: 148 SEQ ID NO: 147 1 + 2a + 2c + 3 without signal peptide (20-260 + 261-320 + 394-445 + 516-628) SEQ ID NO: 150 SEQ ID NO: 149 1 + 2a + 2b + 2c + 3 without signal peptide (20-260 + 261-320 -1 332-387 + 394-445 + 516-628) SEQ ID NO: 152 SEQ ID NO: 151 61: ON QI to HS 1761: ON to HS (OS7-07 + [-68z) aZ + uZ 161: ON UI bis Z61: ON QI to HS (OS7-07 + 96-17) oZ + qZ 681: ON HS 061: ON GHS (96-I6 + I-78Z) qZ + uZ L81: ON QI - HS 881: ON QI biS (OS7-07 + 8Z-67) aZ + UT 581: ON QI - HS 981: ON QI - HS (96- [7 + 8Z-67) qZ + uI (! -178Z + SZ-67) uZ + uT 8I ON UHS 1781: ON UI - HS 181: ON UI - HS Z81: ON - OS7 07 + 8Z I ) aZ + i 6L1: ON UI to 081: ON CU brS (96-17 + 8Z-!) qZ + i 8L 1: ON UI to HS (I-178Z + 8Z-I) uZ + T LL I ON u low SL1 : ON UI OIS 9L1: ON UI OIS (709-67) + Z + ui LI: ON HSHS 17L1: ON UI HSHS (L87-67) Z + Ui ILI: ON UI IS ZLI: ON UI b IS (709-78Z) + Z 691: ## EQU1 ## ## EQU1 ## ## STR2 ## US-AHS (OS7-07) to 91: US-A-1791: ON-CH (96-7), 191: UN-Z9I: UNIDO (I-178Z), 6S1: ON QI-091: ON UI-HS ( L87-I) Z + T LSI ON CHISIS 8S1: ON UIHS (709-887) SSI: ON UI - HS 9S1: ON CUHS (L87-78Z) Z IF ON QI - HS 17S1: ON QI - HS (8Z-I ) T anbipgoalonu aouanbaS anbtaloid aouanbaS T auiJ; at s um ua3 LEZ ON al bis Z: ON CRâqS (609- 886 + 056-806 + 96E-168) + 3Z + qZ su: ON UT ËS 9Z: ON GI S (609-886 + OS6-806 + [88-682) + 3Z + 'ZZ ON Cll to SbZ: ON UT ëS (609-886 + 968- 168 + I88-68Z) + qZ +' Z 1 Z ON UT ëIS ZZ: ON alis (609-886 + OS6-806 + 882-I) + 3Z + 1 6ZZ: ON QI ΔqS OZ: ON ΔqS (609-886 + 968-I68 + 88Z-I) + qZ + I LZZ: ON ## EQU1 ## (609-886 + 188-68Z + 88Z-I) + 'Z + 1 1 SZZ: ON ™ MS 9ZZ: ON (H & SQS (609-886 + OS / 7-806 + 88Z) 66) + 3Z + EI ZZ ON ΔqS 17ZZ: ON (HâHS (609-886 + 968-I68 + 8Z-66) + qZ + 'I IZZ ON CR AqS ZZZ: ON CRâqS (609-886 + I88-68Z + 88Z-66) + 'Z +' I 6IZ nr CRHSH o77: (cTT bgS (609-886 + 882-66) + Ei LTZ: ON UT EIS 8IZ: ON (609-886 + OS6-806) + 3Z SIZ: ON QI-S 9 IZ: ON CRSHS (609-886 + 968-I68) + qZ 1z ON al bas on: ON al down (609- 886 + 188-682) + 'Z 11Z: ON UT ZTZ: ON UT SQ (OS17-8017 + 968- [68 + 188-68Z + 882-66]' 2 + qZ + uZ + ti 60Z: ON UT S ## STR2 ## 66) 3Z + uZ + ti SOZ ON UT ëis 90Z ON UT ëaS (OS6-806 + 968-I68 + 882-66) 3Z + qZ + gi ÒZ ON QI ëES 17OZ ON CU ëaS (968-I68 + I88-682 + 882 -66) qZ + 'Z +' I i0Z: ON UT low ZOZ ON CR AQS (OS17-F0P + 788-682 + 882-1) 3Z + 'Z + I 661: ON AqS 00Z: ON UT HS (OS6-806 + 968 - [68 + 882-I) 3Z + qZ + I L6I: ON QI ëIS 861: ON al AqS (968-I68 + I88-682 + 882-I) qZ + 'Z + i S61 ON GE AqS 96I: ON (H MS (OS6-806 + 968-I68 + 188-682) 3Z + qZ + tz 18Z: On CRIS Z8Z: ON al (609-886 + OS6-06 + 8Z-SZ) such appdad sues .1- ## EQU1 ## + I-b8Z + 8Z-SZ) mals aplTdad sues + uZ + T SLZ: ON ON 9LZ: ON CR-HS (OS6-Ò6 + 96-I6 + I-68Z + 8Z-SZ) Appended with z + qZ + uZ + T LZ ON I have I7LZ: ON have low (OS6-Ò6 + f- / 7g '+ 8Z- T) Ieuâjs app; dad am aZ + uZ + T ILZ ON CII low ZLZ: ON CR low (0Sfi- 06 + 96-I6 + 8- T) p u2Is aplTdad suas aZ + qZ I 69Z: ON low OLZ: ON CR bis (96-I6 + I-68Z + 8Z-ST) [gels app; dad suas qZ + uZ + I L9Z : ON have low 89Z: ON have low (OS6-06 + 8z-SZ) mals aplTdad am aZ + I S9Z ON Cff to 99Z: ON UT low (96-76 + 8Z-SZ.) [Had Is app dad sues qZ + I

I

  9Z: ON (II low b97: ON al low (I-68Z + Sz-ç) IeuIs app; dad sues uZ + I 19Z: ON have low Z9Z ON IQ low (609-88fr + 8Z-SZ) IeuâIs appdad suas + T 6SZ: ON has low 09Z ON al low (L86-SZ) but aplTdad sues Z + T LSZ ON CR low 8SZ: ON have low (8-Sy) mals aplTdad am SSZ: ON CR aaS 9SZ: ON have low (609 -886 + OS6-Ò6 + 96- [6 + I-178i + 8Z-66) + aZ + qZ + eZ + uI SZ: ON have low 17SZ: ON have low (609-886 + OS6-Ò6 + 96-16 + I-68Z + 8Z-I) + aZ + qZ + uZ + TI SZ ON have low ZSZ: ON have low 0709-886 + OS6-Ò6 + I-68Z + 8Z-6t) + aZ + eZ + uq 617Z: ON al down OSZ: ON have low (609-886 + OS6-Ò6 + 96-16 + 8Z-66) + aZ + qZ + uT Lt7Z ON have baS 817Z: ON have low (609-886 + 96-I6 + I -68Z + 8Z-66) + qZ + uZ + uJ St7Z: ON low 917Z: ON have low (609886 + OS6-Ò6 + I -fi8Z + 8Z-I) + aZ + eZ + T bZ ON al low 1717Z: ON have low (609-886 + OS6-06 + 96-I6 + 8Z-I) + aZ + qZ + T IbZ ON have low Z17Z: ON CR low (609-886 + 96-I6 + I-68Z + 8Z-I ) + qZ + eZ + T 6Z: ON Cll low ObZ: ON al low (609-886 + OS6-Ò6 + 96-I6 + I-68Z) + aZ + qZ + uZ 1+ 2a + 2b + 3 without signal peptide (25-283 + 28 4-331 + 341-396 + 488-604) SEQ ID NO: 284 SEQ ID NO: 283 1 + 2b + 2c + 3 without signal peptide (25-283 + 341-396 + 403-450 + 488-604) SEQ ID NO: 286 SEQ ID NO: 285 1 + 2a + 2c + 3 without signal peptide (25-283 + 284-331 + 403-450 + 488-604) SEQ ID NO: 288 SEQ ID NO: 287 1 + 2a + 2b + 2c + 3 without signal peptide (25-283 + 284-331 + 341-396 + 403450 + 488-604) SEQ ID NO: 290 SEQ ID NO: 289 Netrin fragments G Protein sequence Nucleotide sequence 1 (1-295 ) SEQ ID NO: 292 SEQ ID NO: 291 2 (296-438) SEQ ID NO: 294 SEQ ID NO: 293 la (71-295) SEQ ID NO: 296 SEQ ID NO: 295 2a (296-342) SEQ ID NO: 298 SEQ ID NO: 297 2b (373-409) SEQ ID NO: 300 SEQ ID NO: 299 1 + 2a (1-295 + 296-342) SEQ ID NO: 302 SEQ ID NO: 301 SEQ ID NO : 304 SEQ ID NO: 303 1 + 2b (1-295 + 373-409) 1 + 2a + 2b (1-295 + 296-342 + 373-409) SEQ ID NO: 306 SEQ ID NO: 305 + 2 ( 71-295 + 296-438) SEQ ID NO: 308 SEQ ID NO: 307a + 2a (71-295 + 296-342) SEQ ID NO: 310 SEQ ID NO: 309a + 2b (71-295 + 373-) 409) SEQ ID NO: 312 SEQ ID NO: 311 _ SEQ ID NO: 314 S EQ ID NO: 313 2a + 2b (296-342 + 373-409) + 2a + 2b (71-295 + 296-342 + 373-409) SEQ ID NO: 316 SEQ ID NO: 315 1 without signal peptide ( 29-295) SEQ ID NO: 318 SEQ ID NO: 317 1 + 2a without signal peptide (29-295 + 296-342) SEQ ID NO: 320 SEQ ID NO: 319 1 + 2b without signal peptide (29-295 + 373-409) SEQ ID NO: 322 SEQ ID NO: 321 1 + 2a + 2b without signal peptide (29-295 + 296-342 + 373-409) SEQ ID NO: 324 SEQ ID NO: 323 Netrin fragments 3 Sequence Protein Nucleotide Sequence 1 (1-253) SEQ ID NO: 326 SEQ ID NO: 325a (34-253) SEQ ID NO: 328 SEQ ID NO: 327 2 (254-433) _ SEQ ID NO: 329 SEQ ID NO : 330 2a (254-299) SEQ ID NO: 332 SEQ ID NO: 331 2b (73-422) SEQ ID NO: 334 SEQ ID NO: 333 3 (433-580) SEQ ID NO: 336 SEQ ID NO: 335 1 + 2 (1-422) SEQ ID NO: 338 SEQ ID NO: 337 2+ 3 (254-433) SEQ ID NO: 340 SEQ ID NO: 339 1 + 3 (1-253 + 433-580) SEQ ID NO: 342 SEQ ID NO: 341 1 + 2a (1-299) SEQ ID NO: 344 SEQ ID NO: 343 1 + 2b (1- 253 + 373-422) SEQ ID NO: 346 SEQ ID NO: 345 1 + 2a + 2b (1-253 + 254-299 + 373-422 SEQ ID NO: 348 SEQ ID NO: 347 2a + 3 (254-299 + 433-580) SEQ ID NO: 350 SEQ ID NO: 349 2b + 3 (3 73-422 + 433-580) SEQ ID NO: SEQ ID NO: 351 2a + 2b (254-299 + 373-422) SEQ ID NO: 354 SEQ ID NO: 353 2a + 2b + 3 (254-299 + 373-422 + 433-580) SEQ ID NO: SEQ ID NO: 355 1 + 2a + 3 (1-253 + 254-299 + 433-580) SEQ ID NO: 358 SEQ ID NO: 357 1 + 2b + 3 (1-253 + 373-42 + 433- 580) SEQ ID NO: 360 SEQ ID NO: 359 1 + 2a + 2b + 3 (1-253 + 254-299 + 373-422 + 433-580) SEQ ID NO: 362 SEQ ID NO: 361 + 2 ( 34-253 + 254-433) SEQ ID NO: 364 SEQ ID NO: 363a + 3 (34-253 + 433-580) SEQ ID NO: 366 SEQ ID NO: 365 la + 2a (34-253 + 254-) 299) SEQ ID NO: 368 SEQ ID NO: 367a + 2b (34-253 + 373-422) SEQ ID NO: 370 SEQ ID NO: 369 + 2 + 3 34-253 + 254-433 + 433-580 ) SEQ ID NO: 372 SEQ ID NO: 371 SEQ ID NO: 374 SEQ ID NO: 373 the + 2a + 2b (34-253 + 254-299 + 373-422) the + 2a + 3 (34-253 + 254-) 299 + 433-580) SEQ ID NO: 376 SEQ ID NO: 375 + 2b + 3 (34-253 + 373-422 + 433-580) SEQ ID NO: 378 SEQ ID NO: 377 + 2a + 2b + 3 (34-253 + 254-299 + 373-422 + 433-580) SEQ ID NO: 380 SEQ ID NO: 379 Fragments of mutant 4 netrin Protein sequence Nucleotide sequence 1 (1-260) SEQ ID NO: 386 SEQ ID NO: 385 2 (261-515) SEQ ID NO: 388 SEQ ID NO: 387 1 + 2 (1-515) SEQ ID NO: 390 SEQ ID NO: 389 + 2 (32-515) SEQ ID NO: 392 SEQ ID NO: 391 + 2 + 3 (32-) 628) SEQ ID NO: 394 SEQ ID NO: 393 2b (332-387) SEQ ID NO: 396 SEQ ID NO: 395a (32-260) SEQ ID NO: 398 SEQ ID NO: 397 1 + 3 (1- 260 + 516-628) SEQ ID NO: 400 SEQ ID NO: 399 2 + 3 (261-628) SEQ ID NO: 402 SEQ ID NO: 401 1 + 2a (1-260 + 261-320) SEQ ID NO : 404 SEQ ID NO: 403 1 + 2b (1-260 + 332-387) SEQ ID NO: 406 SEQ ID NO: 405 61717: ON CRCS 17: ON CEI 3S (8Z9-9IS + L8-Z + 09Z- I) + qZ + 1 L1717: ON (a 3 S 81717: ON CH AqS (8Z9-9IS + OZ-19Z + 09Z-I) + Z + I 1717 ON CR? MS 91717 ON UI a3S (8Z9-9 [ç + Str6 ## EQU2 ## CR-HSS (9D-91S + OZ- [9Z + 09Z-Z) + 'Z +' i 617: ON QI q S Ott:::::: (8Z9-9 1S + 09Z-Z0 + 'i L17: ON CR 3S 817: ON CEE a3S (8D-91S + L8-Z) + qz S17: ON IQ 917 ON CR OIS (ç -en6 + L8-Z + OZ-19Z + 09Z-Z) 3Z + qZ + uZ + 'T t ON CR a3S 1717: ON CILI 3S (St t% -t6 + L8-Z + OZ-19Z + 09Z-I) 3Z + qZ + uZ + i I t cfi: OM (H q S Z ON ON (((((((((((((((() v via a.aa OIS 1J // VL V. {. + V / V O9ZV (./ -.- z vi

VI-L

  ## EQU1 ## where ## STR2 ## Z) qZ + 'Z +' I SZt: ON (H b3S 9217: ON CU low St P-t'6 + OZ-19Z + 09Z-I) 3Z + 'Z + I Z17: ON QI aqS tZt: ON CLI low St' you have +6 -Z + 092-1) 3Z + qZ + 1 JZt: () No low ZZ17: ON CU low L8-Z + OZ-19Z + 09Z-1) qZ + 'Z + I 6117: ON CFI low Z17: ON CR low Sfrt'-b6 + L8-Z + OZ- [9Z) 3Z + qZ + 'Z Lit: ON (H low 117: ON (H low St't'-f6 + L8-Z) 3Z + qz 117: ON Scream down 117: ON QI OIS (L8-Z + 0Z-19Z) qZ + Z 117: ON down 7117: ON down (St't'-t76 + 09ZZ) 3Z + ui 1117: ON OIS ZI17: ON CR low LS-Z + 09t-Z) qZ + ui 6017: ON CR low 117: ON CR low 0Z-19Z + 09Z-Z) Z + AND L017: ON CH low 017: ON low (Sb- 176 + 092-1) 3Z + I 1 + 2c + 3 (1-260 + 394-445 + 516-628) SEQ ID NO: 452 SEQ ID NO: 451 SEQ ID NO: 454 SEQ ID NO: 453 2a + 2b +3 (261-320 + 332-387 + 516-628) 2b + 2c + 3 (332-387 + 394-445 + 516-628) SEQ ID NO: 456 SEQ ID NO: 455 2a + 2b + 2c + 3 (261-320 + 332-387 + 394-445 + 516-628) SEQ ID NO: 458 _ SEQ ID NO: 457 SEQ ID NO. 460 SEQ ID NO: 459 1 + 2a + 2b + 3 (1-260 + 261-320 + 332-387 + 516-628) 1 + 2b + 2c + 3 (1-260 + 332-387 + 394-445 +516-628) SEQ ID NO: 462 SEQ ID NO: 461 1 + 2a + 2c + 3 (1-260 + 261-320 + 394-445 + 516-628) SEQ ID NO: 464 SEQ ID NO: 463 + 2a + 2b + 3 (32-260 + 261-320 + 332-387 + 516-628) SEQ ID NO: 466 SEQ ID NO: 465a + 2b + 2c + 3 (32-260 + 332-387 + 394-445 +516-628) SEQ ID NO: 468 SEQ ID NO: 467a + 2a + 2c + 3 (32-260 + 261320 + 394-445 + 516-628) SEQ ID NO: 470 SEQ ID NO: 469 1 + 2a + 2b + 2c + 3 (1260 + 261-320 + 332-387 + 394-445 + 516-628) SEQ ID NO: 472 SEQ ID NO: 471a + 2a + 2b + 2c + 3 (32-260 + 261- 320 + 332-387 + 394-445 + 516-628) SEQ ID NO: 474 SEQ ID NO 473 1 without signal peptide (20-260) SEQ ID NO.4 / 0 SEQ ID NO 4/3 1 + 2 without peptide signal (20-516) SEQ ID NO: 478 SEQ ID NO: 477 1 + 3 without signal peptide (20-260 + 516-628) SEQ ID NO: 480 SEQ ID NO: 479 1 + 2a without signal peptide (20- 260 + 261-320) SEQ ID NO: 482 SEQ ID NO 481 1 + 2b without signal peptide (20-260 + 332-387) SEQ ID NO 484 SEQ ID NO: 483 1 + 2c without signal peptide (20-260 + 394-445) SEQ ID NO 486 SEQ ID NO: 485 1 + 2a + 2b without signal peptide (20-260 + 261-320 + 332-387) SEQ ID NO: 488 SEQ ID NO: 487 1 + 2b + 2c without signal peptide (20-260 + 332-387 + 394-445) SEQ ID NO: 490 _SEQ ID NO: 489 1 + 2a + 2c without signal peptide (20-260 + 261320 + 394-445 ) SEQ ID NO: 492 SEQ ID NO: 491 1 + 2a + 2b + 2c without signal peptide (20-260 + 261-320 + 332-387 + 394-445) SEQ ID NO: 494 SEQ ID NO: 493 1+ 2a + 3 without signal peptide (20-260 + 261-320 + 516-628) SEQ ID NO: 496 SEQ ID NO: 495 1 + 2b + 3 without signal peptide (20-260 + 332-387 + 516-628) SEQ ID NO: 498 SEQ ID NO: 497 1 + 2c + 3 without signal peptide (20-260 + 394-445 + 516-628) SEQ ID NO: 500 SEQ ID NO: 499 1 + 2a + 2b + 3 without peptide signal (20-260 + 261-320 + 332-387 + 516-628) SEQ ID NO: 502 SEQ ID NO: 501 1 + 2b + 2c + 3 without signal peptide (20-260 + 332-387 + 394-445 + 516-628) SEQ ID NO: 504 SEQ ID NO: 503 1 + 2a + 2c + 3 without signal peptide (20-260 + 261-320 + 394-445 + 516-628) SEQ ID NO: 506 SEQ ID NO : 505 1 + 2a + 2b + 2c + 3 without p eptide signal (20-260 + 261-320 + 332-387 + 394-445 + 516-628) SEQ ID NO: 508 SEQ ID NO: 507

46 DESCRIPTION OF FIGURES

  Figure 1 corresponds to the test of migration of the smooth muscle cells of the aorta. The cells are counted in 8 fields and the mean and standard deviation are represented on the y-axis. The abscissa axis corresponds to the concentration of the netrin 1 and netrin 4 proteins in ng / ml. The white columns correspond to a concentration of 0 ng / ml; columns with vertical hatching correspond to a concentration of 6 ng / ml; columns with horizontal hatching correspond to a concentration of 18 ng / ml; columns with oblique hatching correspond to a concentration of 55 ng / ml; the gray columns correspond to a concentration of 160 ng / ml and the black columns correspond to a concentration of 500 ng / ml.

  Figure 2 corresponds to the proliferation test of aortic smooth muscle cells. The x-axis corresponds to the concentration of netrin 1 protein, G1 or 4 in ng / ml and the ordinate axis to the optical density measured at 595 nm. The curve with the white circles corresponds to the cells which received netrin G1; the curve with the white squares corresponds to the cells that received netrin 1 and the curve with the black squares corresponds to the cells that received netrin 4.

  Figure 3 shows the effect of an anti-neogenin antibody. The y-axis represents the optical density at 595 nm. The white columns correspond to the case without anti-neogenin antibodies and the black columns correspond to the case where 5 g / ml of anti-neogenin antibodies were injected into the cells.

  Figure 4 shows the protein sequence of netrin 4 (SEQ ID NO: 2) and the corresponding nucleotide sequence (SEQ ID NO: 1).

  Figure 5 shows the protein sequence of netrin 1 (SEQ ID NO: 6) and the corresponding nucleotide sequence (SEQ ID NO: 5).

  Figure 6 shows the protein sequence of netrin 3 (SEQ ID NO: 14) and the corresponding nucleotide sequence (SEQ ID NO: 13).

  Figure 7 shows the protein sequence of netrin G1 (SEQ ID NO: 10) and the corresponding nucleotide sequence (SEQ ID NO: 9).

  Figure 8A shows the protein sequence of mutated Netrin 4 (SEQ ID NO: 382) and Figure 8B shows the corresponding nucleotide sequence (SEQ ID NO: 384).

  EXPERIMENTAL PART Materials: The Netrin 1 (SEQ ID NO: 6), Netrin 4 (SEQ ID NO: 2), Netrin 3 (SEQ ID NO: 14) and Netrin Gi (SEQ ID NO: 10) molecules are recombinant proteins.

  The 165 amino acid isoform of VEGF 'is produced by infection of SF9 insect cells with a recombinant baculovirus containing the corresponding cDNA (Plouet et al., 1997).

  Aortic smooth muscle cells (Clonetics) were maintained in DMEM medium supplemented with 15% heat inactivated fetal calf serum (FCS), 100 μg / ml penicillin and 100 μg / ml streptomycin at 37 ° C. in 10% of CO2. Stem cultures received 2 ng / ml FGF every even day.

  Migration tests Smooth muscle cells (VSM) are inoculated into high density 4 cm2 wells (50,000 cells / well). When the monolayer is confluent, the proliferation is stopped by incubation overnight, in the presence of M199 (Life Sciences) containing 2% FCS. An injury is then performed in the monolayer using a foam scraper, to delimit a free surface of any cell. The monolayers are then washed 3 times with M199 to remove non-adherent cells. A photograph is then taken to delimit the surface before any cell migration. The wells are then incubated with M199 and 2% FCS alone or in the presence of 50 ng / ml of VEGF in the presence of variable concentrations of Netrin 4 (NET-4) or Netrin 1 (NET-1). After 24 hours the wells are washed 3 times and stained at May-Grunwald-Giemsa and photographed. The photographs taken before and after the experiment are then superimposed to allow counting of the cells having migrated.

  The results of these tests are shown in Figure 1.

  From Figure 1 it can be seen that netrin 1 and netrin 4 have a positive effect on the migration of MSM. Indeed, netrin 1 and netrin 4 stimulate the migration of smooth muscle cells and 50% of the maximum effect is obtained with a concentration of 20 ng / ml of NET-4.

  Proliferation assays 96-well culture plates were inoculated with 2,000 VSM cells per well in DMEM supplemented with 10% FCS. The cells were stimulated or not with different concentrations of netrin 1, netrin G1 or netrin 4.

  In some wells 5 g / ml anti-neogenin antibody was added. After 5 days, the wells were rinsed gently with DMEM and the cells were fixed in 1% glutaldehyde for 20 minutes at room temperature. The fixed cells were quantified by crystal violet incorporation (Kueng et al., 1989): the cells were incubated in 0.1% crystal violet (Sigma) for 20 minutes at room temperature, the unincorporated dye was removed washing the wells thoroughly with large amounts of water and the incorporated crystallized violet dye was then solubilized with 100 l of 10% acetic acid per well. Optical density readings were performed at 595 nm. Similar results were obtained in three separate experiments (see Figure 3). The values shown are average optical densities of 6 SD wells.

  The netrin 1, netrin G el netrin 4 proteins used alone have a significant effect on proliferation in a dose-dependent fashion. 50% of the maximum effect is obtained with a concentration of 20 ng / ml.

  FIG. 3 shows that the addition of anti-neogenin antibodies does not reverse the proliferation inhibitory activity induced by netrin 4.

  Production of Anti-Idiotypic Antibodies Initially, a netrin neutralizing antibody 1, 3, G or 4 or one of its abovementioned fragments (SEQ ID NO: 28 to 380) is prepared by injecting an animal, in particular a mouse, said netrin or said fragment mixed with complete Freund's adjuvant (1 volume per volume netrin or netrin fragment). An amount of netrin or netrin fragment between 10 and 500 g / kg of body weight will be chosen to immunize the animal. The same operation is carried out at 15 and 30 days apart, except that the complete adjuvant is replaced by incomplete adjuvant. At day 40 a bleeding is practiced, the serum is separated and the immunoglobulins are purified by any usual fractionation method, in particular ammonium sulfate precipitation, affinity chromatography for protein A or G. The neutralizing activity of the proteins is measured. immunoglobulins by any described test (for example, in the case of netrin 4 or a fragment thereof, binding of labeled netrin 4 to the extracellular domain of any of its receptors, proliferation, migration, cellular adhesion). Thus, a batch of antibodies will be said to be neutralizing when it has the capacity to inhibit the interaction of netrin 1, 3, 4 or G with either the extracellular domain of dcc, or of neogenin, or of UNC5H1, or of UNC5H2 either UNC5H3 or UNC5H4.

  Secondly, anti-idiotypic antibodies of netrin 1, 3, G or 4 or of one of their fragments are prepared by injecting subcutaneously 1-100 g of the preparation of neutralizing immunoglobulins into mice. the activity of said netrin or said fragment previously described in combination with 100 l of adjuvant, including Freund's complete adjuvant (Sigma). The injection is repeated 15, 30 and 45 days later. Fifty-five days after the first injection, mice were injected with 10 g of the same antibody intraperitoneally. Fifty-eight days after the first injection, the mice are sacrificed and their spleens are removed and dilacerated in ISCOVE medium to release the splenocytes. The splenocytes are fused with mouse myeloma cells, including AG8X 63 cells (Kearney et al., 1979), and incubated at 100,000 cells / well. The melting is carried out by adding 20 times 50 l of polyethylene glycol (PEG) at 30 seconds intervals. Four ml of ISCOVE medium preheated to 37 ° C. are then added dropwise to the cell suspension, and after an incubation period of 4 minutes at 37 ° C., 4 ml are added. The suspension is centrifuged and the cell pellet is then taken up in 100 ml of ISCOVE medium supplemented with 20% fetal calf serum and 1X HAT (50X: 5 mM hypoxanthine, 20 M Aminopterin and 0.8 mM Thymidine) and distributed to reason of 100 l per well on the macrophages. After 5 days, 100 l of HAT medium are added, and between 8 and 14 days the conditioned medium of each hybridoma is removed to measure by ELISA the antibodies directed against the antibodies having served as immunogenic agent, ie the antibodies Anti-netrin 1, 3, G or 4. The activity of the anti-idiotypic antibodies is then measured by an ELISA test: The Fab fragments of anti-netrin immunoglobulin 1, 3, G or 4, prepared by any conventional technique, in particular Papain digestion was immobilized on microtiter plates (0.1-20 μg / ml in 50 mM carbonate buffer pH 9.6). After saturation of the nonspecific sites by a solution of serum albumin diluted to 5 mg / ml in the same buffer, the supernatants of hybridoma cultures are added half diluted in PBS buffer (phosphate buffer solution) containing 0.05% of Tween 2.0. After rinsing, the antiidiotypic antibodies are revealed by adding an appropriate concentration of mouse anti-Fc antibody coupled to peroxidase. The amount of bound anti-idiotypic antibody is then measured by peroxidase revelation and is proportional to the intensity of the colorimetric reaction.

  Hybridomas selected by their ability to secrete antibodies directed against anti-netrin 1, 3, G or 4 antibodies are then cloned, i.e. the cells are seeded under limiting dilution conditions (5 cells / ml) in a volume of 0.1 ml per well. The medium is changed after 10 days. After 15 days, some wells contain foci of cells that have multiplied from the cell seeded initially, so all these cells are identical and are from the same clone. When the area occupied by the cells represents at least half of the total area of the well, the medium is removed and analyzed as previously by an anti-NOV Fab ELISA. At this stage, the antibody producing clones can be selected and their specificity known.

  A second ELISA is then used: goat immunoglobulins directed against the Fc domains of human IgGs are incubated on microtiter plates (0.1-20 μg / ml in 50 mM carbonate buffer pH 9.6). After saturation of the nonspecific sites by a solution of serum albumin diluted to 5 mg / ml in the same buffer, the proteins containing the extracellular domains of the netrin receptors fused to a Fc sequence of human IgG are immobilized on the microtiter plates ( incubation at a concentration of between 1 and 100 g / ml). The supernatants of hybridoma cultures are added half diluted in PBS buffer containing 0.05% Tween 20. After rinsing, the antiidiotypic antibodies are revealed by adding an appropriate concentration of anti-mouse Fc antibody coupled to peroxidase. The amount of bound anti-idiotypic antibody is then measured by peroxidase revelation and is proportional to the intensity of the colorimetric reaction.

  Once the clones have been identified, their monoclonal nature is asserted by the conventional operation of inoculating a 96-well plate with cells from the same clone diluted under limiting conditions as previously. Secreting clones must therefore all secrete an antibody of the same specificity for this monoclonal antibody to be declared. A third cloning is then performed exactly under the same conditions to ensure that the clones are well monoclonal.

  The monoclonal anti-idiotypic antibodies are screened by a battery of tests, in particular by an ELISA test on extracellular domains of neogenin, UNC5H4, neuropilin 1, inhibition of the proliferation or migration of HUAEC cells, stimulation of the proliferation or migration of smooth muscle cells (VSM) and pericytes, or in vivo measurement tests of anti-angiogenic activity or inhibition of atherosclerotic plaque development or reduction of the size of the aneurysm in an experimental model.

  The anti-idiotypic antibodies thus obtained are therefore mimics of netrin domains. The goal is to make an "internal image" of a Netrin domain and thus to be able to obtain an antibody binding a netrin receiver without binding all the receptors.

  Once the specificity is attested, the agonist or antagonist function of this given antibody is determined by measuring its activity on cells, for example: UNC5H4 agonist: stimulates the functions of the VSM without inhibiting or stimulating the functions of the netrin on arterial endothelial cells Human umbilicals (HUAEC) or antagonist of UNC5H4: inhibits the stimulatory action of netrin on MSM functions without inhibiting or stimulating netrin functions on HUAEC.

  The general interest of these antibodies is to be able to mimic a netrin function on a cellular target without affecting other targets. Thus, it would be interesting to stimulate pericyte functions without inducing endothelial cell apoptosis or inhibiting their migration, proliferation or differentiation in certain pathologies such as: age-related macular degeneration, diabetic retinopathies, early stage where the. scarcity of pericytes precedes neovascularization, neovascular glaucoma, rheumatoid arthritis, psoriasis, especially psoriatic arthritis, angiomas, atherosclerosis, obesity, intestinal malformations, Crohn's disease, vascular dementia, vascular cortices of which Cadasil is an example, Alzheimer's disease, aneurysms and vascular dissections.

  REFERENCES - Arnal JF, Gourdy P, Garmy-Susini B, Delmas E, Bayard F (2003) Usefulness 5 of experimental models to understand the vascular effects of estrogens. Med Sci (Paris). 19 (12): 1226-32; Brooks PC, Clark RA, Cheresh DA (1994) Requirement of Vascular Integrin Alpha v beta 3 for angiogenesis. Science, 264, 569-71; Celerier J, Cruz A, Lamande N, Gasc JM, Corvol P (2002) Angiotensinogen and its cleaved derivatives inhibit angiogenesis. Hypertension. 39 (2): 224-8; Cooper HM, Gad JM, Keeling SL (1999) The Deleted in Colorectal Cancer netrin guidance system: a molecular strategy for neuronal navigation. Clin Exp Pharmacol Physiol. 26 (9): 749-51; Corset V, Nguyen-Ba-Charvet KT, Forcet C, Moyse E, Chedotal A, Mehlen P (2000) Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor. Nature. 407: 747-50; Hutchings H, Ortega N, Plouet J (2003) Extracellular matrix bound vascular endothelial growth factor promotes endothelial cell adhesion, migration and survival through integrin ligation. FASEB J. 17: 1520-1522; Jain RK, Schlenger K, Hockel M, Yuan F (1997) Quantitative angiogenesis assays: progress and problems. Nat Med. 3 (11): 1203-8; Kearney JF, Radbruch A, Liesegang B, Rajewsky K (1979) A new mouse myeloma cell line that has lost immunoglobulin expression but permits the construction of antibody-secreting hybrid cell lines. J. Immunol. 123, 1548-50; Kueng W, Silber E, Eppenberger U (1989) Quantification of cell cultures on 96-well plates. Anal. Biochem, 182 (1): 16-9; Livesey FJ (1999) Netrin and netrin: receptors. Cell Mol Life Sci, 56 (1-2): 62-8; Lu X, Noble F, Yuan L, Jiang Q, Lafarge B, Sugiyama D, Breant C, Claes F, De Smet F, Thomas JL, Autiero M, Carmeliet P, Tessier-Lavigne M, Eichmann A (2004) The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system. Nature. 432: 179-186; Mehlen P, Mazelin L (2003) The dependence receptors DCC and UNC5H as a link between neuronal guidance and survival. Rio! Cell. 95 (7): 425-36; Nakashiba T, Ikeda T, Nishimura S, Tashiro K, Honjo T, Culotti JG, Itohara S (2000) Netrin-G1: a novel glycosyl phosphatidylinositol-linked mammalian netrin that is functionally divergent from classical netrins. JNeurosci. (17): 6540-50; Nakashiba T, Nishimura S, Ikeda T, Itohara S (2002) Complementary expression and neurite outgrowth activity of netrin-G subfarnily members. Mech Dev.

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Claims (6)

  1. Use of a protein characterized in that it comprises or consists of: * netrin 4, represented by the sequence SEQ ID NO: 2 or SEQ ID NO: 4, or * a fragment of one of these protein, said fragment being represented by one of the sequences SEQ ID NO: 2n, n varying from 8 to 76, for the preparation of a medicament intended for the prevention or treatment of non-tumoral pathologies related to, or caused by, scarcity of pericytes or smooth muscle cells.   2. Use according to claim 1, characterized in that non-tumoral pathologies related to or caused by a rarefaction of pericytes or smooth muscle cells, and requiring activation of proliferation or migration of pericytes or muscle cells. smooth, are selected from: age-related macular degeneration, diabetic retinopathies, neovascular glaucoma, rheumatoid arthritis, psoriasis, especially psoriatic arthritis, angiomas, atherosclerosis, obesity, intestinal malformations , Crohn's disease, vascular dementia, vascular subcorticals including Cadasil is an example, Alzheimer's disease, degenerative bone diseases and fractures, and aneveysms and vascular dissections.   3. Use according to claim 1 or 2, characterized in that the activation activity of the proliferation or migration of pericytes or smooth muscle cells is measured according to the proliferation or migration test, and in that this Activation activity corresponds to at least 120% of the cells obtained in the absence of the protein.   4. Use according to one of claims 1 to 3, netrin protein 4, represented by the sequence SEQ ID NO: 2 or SEQ ID NO: 4, as active substance.   5. Use according to one of claims 1 to 3, a netrin, including netrin protein 4, represented by the sequence SEQ ID NO: 2 or SEQ ID NO: 4, for the preparation of a drug susceptible of be administered from about 0.1 to about 20 mg / kg / day, especially intravenously, subcutaneously, systemically, intravitreously, locally by infiltration or via eye drops, possibly associated with electropermination.   6. Use according to one of claims 1 to 3, the fragment of the netrin 4 protein represented by SEQ ID NO: 20, or a protein or a peptide containing the sequence SEQ ID NO: 20, or for that protein or peptide containing this fragment.