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1. WO2007008712 - ANTI-ALPHA V BETA 6 ANTIBODIES AND USES THEREOF

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

WHAT IS CLAIMED IS:

1. A humanized antibody that specifically binds to αvβ6 comprising a heavy chain variable domain sequence of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2.

2. The humanized antibody of claim 1, wherein the heavy chain variable domain comprises complementarity determining regions (CDR) defined by amino acid residues 31-35 (CDRl), 50-65 (CDR2) and 98-109 (CDR3) of SEQ ID NO: 1.

3. The humanized antibody of claim I5 wherein the light chain variable domain comprises complementarity determining regions (CDR) defined by amino acid residues 24-35 (CDRl), 51-57 (CDR2) and 90-98 (CDR3) of SEQ ID NO: 2.

4. The humanized antibody of claim 1, wherein the heavy chain variable domain comprises framework regions (FR) defined by amino acid residues 1-30 (FRl), 36-49 (FR2), 66-97 (FR3) and 110-120 (FR4) of SEQ ID NO: 1.

5. The humanized antibody of claim 1, wherein the light chain variable domain comprises framework regions (FR) defined by amino acid residues 1-23 (FRl), 36-50 (FR2), 58-89 (FR3) and 99-108 (FR4) of SEQ ID NO: 2.

6. The humanized antibody according to any one of claims 1-5, wherein said antibody comprises at least one amino acid substitution in the heavy chain or light chain variable domain in the CDRl sequences, CDR2 sequences, CDR3 sequences or framework sequences.

7. The humanized antibody of claim 6, wherein said antibody comprises at least one of the following amino acid substitutions in the heavy chain variable domain consisting of Q3M and N74S of SEQ ID NO: 1.

8. The humanized antibody of claim 7, wherein said antibody comprises the following amino acid substitutions in the heavy chain variable domain (HVl) consisting of Q3M and N74S of SEQ TD NO: 1.

9. The humanized antibody of claim 7, wherein said antibody comprises the following amino acid substitution in the heavy chain variable domain (HV2) consisting of N74S of SEQ E) NO: 1.

10. The humanized antibody of claim 7, wherein said antibody comprises in the heavy chain variable domain (HV3) the sequence of SEQ ID NO: 1.

11. The humanized antibody of claim 6, wherein said antibody comprises at least one amino acid substitution in the light chain variable domain selected from the group consisting of ElQ, L47W, 158 V, A60V and Y87F of SEQ ID NO: 2.

12. The humanized antibody of claim 11, wherein said antibody comprises amino acid substitutions in the light chain variable domain (LVl) consisting of L47W, 158 V, A60V and Y87F of SEQ ID NO: 2.

13. The humanized antibody of claim 11, wherein said antibody comprises amino acid substitutions in the light chain variable domain (L V2) consisting of L47W and I58V of SEQ ID NO: 2.

14. The humanized antibody of claim 11, wherein said antibody comprises amino acid substitutions in the light chain variable domain (L V3) consisting of consisting of L47W of SEQ ID NO: 2.

15. The humanized antibody of claim 11, wherein said antibody comprises amino acid substitutions in the light chain variable domain (L V4) consisting of consisting of ElQ and L47W of SEQ E) NO: 2.

16. The humanized antibody of claim 11, wherein said antibody comprises in the light chain variable domain (LV5) the sequence of SEQ ED NO: 2.

17. A humanized antibody that specifically binds to αvβ6 comprising a heavy chain variable domain sequence of SEQ ED NO: 1 (HV3) and a light chain variable domain of SEQ ID NO: 2 (LV5).

18. The humanized antibody of claim 1 or claim 17, wherein the complementarity determining regions (CDR) are derived from the murine 3G9 antibody.

19. The humanized antibody claim 1 or claim 17, wherein the antibody can compete with murine 3G9 antibody for binding to αvβe.

20. The humanized antibody of claim 1 or claim 17, wherein the antibody is produced by a recombinant vector comprising a nucleic acid encoding said antibody.

21. The humanized antibody of claim 20, wherein the recombinant vector is a plasmid selected from the group consisting of pKJS195, pKJS189 and pKJS196.

22. The humanized antibody of claim 21, wherein the plasmid pKJS195 comprises SEQ ID NO: 5.

23. The humanized antibody of claim 21, wherein the plasmid pKJS189 comprises SEQ ID NO: 6.

24. The humanized antibody of claim 21, wherein the plasmid pKJS196 comprises SEQ ID NO: 7.

25. A humanized antibody having specificity for the epitope recognized by any one of the antibodies of claims 1 and 17.

26. A humanized antibody which specifically binds αvβ6 comprising:
(a) a humanized light chain comprising three light chain complementarity determining regions (CDR) from the murine 3G9 antibody and a light chain variable region framework (FR) sequence from a human immunoglobulin light chain; and
(b) a humanized heavy chain comprising three heavy chain complementarity determining regions (CDR) from the murine 3G9 antibody and a heavy chain variable region framework (FR) sequence from a human immunoglobulin heavy chain.

27. An isolated nucleic acid molecule comprising a coding sequence for any one of SEQ ID NOs: 1-5.

28. An isolated polypeptide comprising an amino acid sequence of any one of SEQ ID NOs: 1-5.

29. A recombinant vector comprising the nucleic acid molecule of claim 27.

30. The recombinant vector of claim 29, further comprising a fused gene encoding a humanized immunoglobulin light chain, said gene comprising a nucleotide sequence encoding a CDR derived from a light chain of a nonhuman antibody having binding specificity for αvβ6 and a framework region derived from a light chain of human origin.

31. The recombinant vector of claim 30, wherein the nonhuman antibody is murine 3G9 antibody.

32. The recombinant vector of claim 30, wherein the vector is plasmid pKJS195.

33. The recombinant vector of claim 29, further comprising a fused gene encoding a humanized immunoglobulin heavy chain, said gene comprising a nucleotide sequence encoding a CDR derived from a heavy chain of a nonhuman antibody having binding specificity for αvβό and a framework region derived from a heavy chain of human origin.

34. The recombinant vector of claim 33, wherein the nonhuman antibody is murine 3G9 antibody.

35. The recombinant vector of claim 33, wherein the vector is plasmid pKJS189.

36. The recombinant vector according of claim 33, wherein the vector is plasmid pKJS196.

37. A host cell comprising the recombinant vector of any one of claims 29-36.

38. A composition for preventing or treating a disease mediated by αvβ6 in a mammal, comprising the antibody of any one of claims 1,17 and 26, and a pharmaceutically acceptable carrier.

39. The composition of claim 38, wherein the antibody is conjugated to a cytotoxic agent.

40. A method of preparing a humanized antibody comprising culturing the host cell of claim 37 under conditions appropriate for expression of a humanized antibody, wherein humanized antibody chains are expressed and a humanized antibody is produced.

41. The method of claim 40, further comprising isolating the humanized antibody.

42. The method of claim 40, wherein the host cell is a CHO cell.

43. A method of treating a subject having or at risk of having a disease mediated by αvβ6, comprising administering to the subject the composition of claim 38, thereby alleviating or postponing the onset of the disease.

44. The method of claim 43, wherein the subject is human.

45. The method of claim 43, wherein the disease is fibrosis.

46. The method of claim 45, wherein the fibrosis is scleroderma, scarring, liver fibrosis, kidney fibrosis, or lung fibrosis.

47. The method of claim 43, wherein the disease is psoriasis.

48. The method of claim 43, wherein the disease is cancer.

49. The method of claim 48, wherein the cancer is epithelial cancer.

50. The method of claim 48, wherein the cancer is oral, skin, cervical, ovarian, pharyngeal, laryngeal, esophageal, lung, breast, kidney, or colorectal cancer.

51. The method of claim 48, wherein the disease is Alport's Syndrome.

52. A humanized antibody that specifically binds to αvβ6 comprising a heavy chain variable domain sequence of SEQ ID NO: 3 and a light chain variable domain of SEQ ID NO: 4.

53. The humanized antibody of claim 52, wherein the heavy chain variable domain comprises complementarity determining regions (CDR) defined by amino acid residues 31-35 (CDRl), 50-66 (CDR2) and 99-115 (CDR3) of SEQ ID NO: 3.

54. The humanized antibody of claim 52, wherein the light chain variable domain comprises complementarity determining regions (CDR) defined by amino acid residues 24-38 (CDRl), 54-60 (CDR2) and 93-101 (CDR3) of SEQ ID NO: 4.

55. The humanized antibody of claim 52, wherein the heavy chain variable domain comprises human framework regions (FR) defined by amino acid residues 1-30 (FRl), 36-49 (FR2), 67-98 (FR3) and 116-126 (FR4) of SEQ ID NO: 3.

56. The humanized antibody of claim 52, wherein the light chain variable domain comprises human framework regions (FR) defined by amino acid residues 1-23 (FRl), 39-53 (FR2), 61-92 (FR3) and 102-111 (FR4) of SEQ ID NO: 4.

57. The humanized antibody of any one of claims 52-56, wherein said antibody comprises at least one amino acid substitution in the heavy chain or light chain variable domain in the CDRl sequences, CDR2 sequences, CDR3 sequences or framework sequences.

58. The humanized antibody of claim 57, wherein said antibody comprises at least one of the following amino acid substitutions in the heavy chain variable domain consisting of A24G, G26S, Q39L, M48I, V68A, R72V and T74K of SEQ ID NO: 3.

59. The humanized antibody of claim 58, wherein said antibody comprises the amino acid substitution in the heavy chain variable domain (HVl ') consisting of A24G, G26S, Q39L, M48I, V68A, R72V and T74K of SEQ ID NO: 3.

60. The humanized antibody of claim 58, wherein said antibody comprises the amino acid substitution in the heavy chain variable domain (EYT) consisting of M48I, V68A, R72V and T74K of SEQ ID NO: 3.

61. The humanized antibody of claim 58, wherein said antibody comprises amino acid substitution in the heavy chain variable domain (HV3') consisting of V68A, R72V and T74K of SEQ ID NO: 3.

62. The humanized antibody of claim 57, wherein said antibody comprises at least one amino acid substitution in the light chain variable doraain selected from the group consisting of ElD, L46F and Y49K of SEQ ID NO: 4.

63. The humanized antibody of claim 62, wherein said antibody comprises amino acid substitutions in the light chain variable domain (LVl ') consisting of ElD, L46F and Y49K of SEQ ID NO: 4.

64. The humanized antibody of claim 62, wherein said antibody comprises amino acid substitutions in the light chain variable domain (LV2') consisting of L46F and Y49K of SEQ ID NO: 4.

65. The humanized antibody of claim 62, wherein said antibody comprises an amino acid substitution in the light chain variable domain (L V3') consisting of Y49K of SEQ ID NO: 4.

66. The humanized antibody of any one of claims 52-56, wherein the complementarity determining regions (CDR) are derived from the murine 8G6 antibody.

67. The humanized antibody any one of claims 52-56, wherein the antibody can compete with murine 8G6 antibody for binding to αvβ6.

68. An isolated nucleic acid molecule comprising a coding sequence for any one of SEQ ID NOs: 3-4.

69. An isolated polypeptide comprising an amino acid sequence of any one of SEQ ID NOs: 3-4.

70. A recombinant vector comprising the nucleic acid molecule of claim 68.

71. The recombinant vector of claim 70, further comprising a fused gene encoding a humanized immunoglobulin light chain, said gene comprising a nucleotide sequence encoding a CDR derived from a light chain of a nonhuman antibody having binding specificity for αvβ6 and a framework region derived from a light chain of human origin.

72. The recombinant vector of claim 71, wherein the nonhuman antibody is murine 8G6 antibody.

73. The recombinant vector of claim 70, further comprising a fused gene encoding a humanized immunoglobulin heavy chain, said gene comprising a nucleotide sequence encoding a CDR derived from a heavy chain of a nonhuman antibody having binding specificity for αvβ6 and a framework region derived from a heavy chain of human origin.

74. The recombinant vector of claim 73, wherein the nonhuman antibody is murine 8G6 antibody.

75. A host cell comprising the recombinant vector of any one of claims 70-74.

76. A composition for preventing or treating a disease mediated by αvβ6 in a mammal, comprising the antibody of any one of claims 52-56 and a pharmaceutically acceptable carrier.

77. The composition of claim 76, wherein the antibody is conjugated to a cytotoxic agent.

78. A method of preparing a humanized antibody comprising culturing the host cell of claim 75 under conditions appropriate for expression of a humanized antibody, wherein humanized antibody chains are expressed and a humanized antibody is produced.

79. The method of claim 78, further comprising isolating the humanized antibody.

80. The method of claim 78, wherein the host cell is a CHO cell.

81. A method of treating a subject having or at risk of having a disease mediated by αvβ6, comprising administering to the subject the composition of claim 76, thereby alleviating or postponing the onset of the disease.

82. The method of claim 81, wherein the subject is human.

83. The method of claim 81 , wherein the disease is fibrosis.

84. The method of claim 81, wherein the disease is cancer.

85. The method of claim 81, wherein the disease is Alport's Syndrome.

86. A humanized antibody comprising a heavy chain variable domain version 3 (HV3) produced by a recombinant vector comprising plasmid pKJS189 (SEQ ID NO: 6) and a light chain variable domain version 5 (LV5) produced by a recombinant vector comprising plasmid pKJS195 (SEQ ID NO: 5).

87. A humanized antibody comprising an aglycosyl heavy chain variable domain version 3 (a-HV3) produced by a recombinant vector comprising plasmid pKJS196 (SEQ ID NO: 7) and a light chain variable domain version 5 (LV5) produced by a recombinant vector comprising plasmid pKJS195 (SEQ ID NO: 5).

88. A method of reducing or preventing the metastasis of a primary tumor to a secondary location in a patient, comprising administering to said patient a therapeutically effective amount of one or more ligands that binds to one or more subunits of integrin αvβ6 on one or more cells in said primary tumor, wherein the binding of said ligand to said integrin results in the death, chemosensitivity or decreased invasiveness of said tumor cell.

89. The method of claim 88, wherein said tumor is a carcinoma.

90. The method of claim 89, wherein said carcinoma is an adenocarcinoma.

91. The method of claim 89, wherein said carcinoma is selected from the group consisting of a breast carcinoma, an endometrial carcinoma, a pancreatic carcinoma, a colorectal carcinoma, a lung carcinoma, an ovarian carcinoma, a cervical carcinoma, a prostatic carcinoma, a liver carcinoma, an esophageal carcinoma, a head and neck carcinoma, a stomach carcinoma and a splenic carcinoma.

92. The method of claim 89, wherein said carcinoma is a breast carcinoma.

93. The method of claim 92, wherein said breast carcinoma is an in situ breast carcinoma.

94. The method of claim 93, wherein said in situ breast carcinoma is selected from the group consisting of a ductal carcinoma in situ (DCIS) and a lobular carcinoma in situ (LCIS).

95. The method of claim 89, wherein said carcinoma is an endometrial carcinoma.

96. The method of claim 89, wherein said carcinoma is a pancreatic carcinoma.

97. The method of claim 89, wherein said carcinoma is a colorectal carcinoma.

98. The method of claim 89, wherein said carcinoma is a cervical carcinoma.

99. The method of claim 89, wherein said carcinoma is a lung carcinoma.

100. The method of claim 88, wherein said ligand that binds to an αvβ6 integrin is an antibody or an αvβ6 epitope-binding fragment thereof.

101. The method of claim 100, wherein said antibody is a monoclonal antibody.

102. The method of claim 101, wherein said monoclonal antibody is a chimeric, primatized or humanized monoclonal antibody.

103. The method of claim 101, wherein said monoclonal antibody is selected from the group consisting of 2Al, 2E5, 1A8, 2B10, 2Bl, IGlO, 7G5, 1C5, 8G6, 3G9, 10D5 and CSβ6.

104. The method of claim 101, wherein said monoclonal antibody is 3G9.

105. The method of claim 101, wherein said monoclonal antibody is 8G6.

106. The method of claim 101, wherein said monoclonal antibody is a humanized monoclonal antibody.

107. The method of claim 106, wherein said humanized monoclonal antibody is hu3G9 (BGOOOIl).

108. The method of claim 106, wherein said humanized monoclonal antibody is hu8G6

109. The method of claim 88, wherein said ligand is conjugated with at least one cytotoxic compound.

110. The method of claim 88, wherein said ligand is administered to said patient in conjunction with the administration to said patient of at least one cytotoxic compound.

111. The method of claim 109 or claim 110, wherein said cytotoxic compound is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, paclitaxel, melphalan, doxorubicin, methotrexate, 5-fluorouracil, etoposide, mechlorethamine, cyclophosphamide, bleomycin, a calicheamicin, a maytansine, a trichothene, CC 1065, diphtheria A chain, Pseudomonas aeruginosa exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, an Aleuritesfordii protein, a dianthin protein, a Phytolaca americana protein, momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, a tricothecene, a ribonuclease, and a deoxyribonuclease.

112. The method of claim 109 or claim 110, wherein said cytotoxic compound is selected from the group consisting of a radioisotope and a prodrug-activating enzyme.

113. The method of claim 112, wherein said radioisotope is selected from the group consisting Of 211At, 131I, 125I, 90Y, 186Re, 188Re, 153Sm, 212Bi, 32P, and radioactive isotopes of Lu.

114. The method of claim 112, wherein said prodrug-activating enzyme is selected from the group consisting of alkaline phosphatase, arylsulfatase, cytosine deaminase, a protease, a D-alanylcarboxypeptidase, a carbohydrate-cleaving enzyme, P-lactamase and a penicillin amidase.

115. The method of claim 88, wherein said ligand is administered to said patient in the form of a pharmaceutical composition comprising said ligand and one or more pharmaceutically acceptable carriers or excipients.

116. The method of claim 88 or claim 115, wherein said ligand or composition is administered to said patient via a route selected from the group consisting of oral administration, parenteral administration, intracranial administration, intrapulmonary administration and intranasal administration.

117. The method of claim 116, wherein said ligand or composition is administered to said patient via a parenteral route selected from the group consisting of intramuscular administration, intravenous administration, intraarterial administration and subcutaneous administration.

118. The method of claim 117, wherein said parenteral route comprises administering said ligand or composition to said patient via injection.

119. A method of diagnosing a carcinoma that is more likely to progress to an invasive carcinoma, comprising:
(a) obtaining from a patient a cancerous epithelial tissue sample comprising a tumor or a portion thereof, and a noncancerous epithelial tissue sample;
(b) contacting said tissue samples with one or more ligands that binds to one or more subunits of integrin αvβ6; and
(c) determining the level of expression of integrin αvβ6 in said tissue samples,
wherein an increase in the level of expression of integrin αvβ6 in said cancerous tissue sample relative to the level of expression of integrin αvβ6 in said noncancerous tissue sample indicates the presence in said patient of a carcinoma that is more likely to progress to an invasive carcinoma.

120. The method of claim 119, wherein said tumor is a carcinoma.

121. The method of claim 120, wherein said carcinoma is an adenocarcinoma.

122. The method of claim 120, wherein said carcinoma is selected from the group consisting of a breast carcinoma, an endometrial carcinoma, a pancreatic carcinoma, a colorectal carcinoma, a lung carcinoma, an ovarian carcinoma, a cervical carcinoma, a prostatic carcinoma, a liver carcinoma, an esophageal carcinoma, a head and neck carcinoma, a stomach carcinoma and a splenic carcinoma.

123. The method of claim 122, wherein said carcinoma is a breast carcinoma.

124. The method of claim 123, wherein said breast carcinoma is an in situ breast carcinoma.

125. The method of claim 124, wherein said in situ breast carcinoma is selected from the group consisting of a ductal carcinoma in situ (DCIS) and a lobular carcinoma in situ (LCIS).

126. The method of claim 124, wherein said carcinoma is an endometrial carcinoma.

127. The method of claim 120, wherein said carcinoma is a pancreatic carcinoma.

128. The method of claim 120, wherein said carcinoma is a colorectal carcinoma.

129. The method of claim 120, wherein said carcinoma is a cervipal carcinoma.

130. The method of claim 120, wherein said carcinoma is a lung carcinoma.

131. The method of claim 119, wherein said ligand that binds to an αvβ6 integrin is an antibody or an αvβ6 epitope-binding fragment thereof.

132. The method of claim 131, wherein said antibody is a monoclonal antibody.

133. The method of claim 132, wherein said monoclonal antibody is a chimeric, primatized or humanized monoclonal antibody.

134. The method of claim 132, wherein said monoclonal antibody is selected from the group consisting of 2Al, 2E5, 1A8, 2B10, 2Bl, IGlO, 7G5, 1C5, 8G6, 3G9, 10D5 and CSβ6.

135. The method of claim 132, wherein said monoclonal antibody is 3G9.

136. The method of claim 132, wherein said monoclonal antibody is 8G6.

137. The method of claim 132, wherein said monoclonal antibody is a humanized monoclonal antibody.

138. The method of claim 137, wherein said humanized monoclonal antibody is hu3G9 (BGOOOl 1).

139. The method of claim 137, wherein said humanized monoclonal antibody is hu8G6

140. The method of claim 119, wherein said ligand is conjugated with at least one detectable label.

141. The method of claim 140, wherein said detectable label is selected from the group consisting of a chromogenic label, an enzyme label, a radioisotopic label, a non-radioactive isotopic label, a fluorescent label, a toxic label, a chemiluminescent label, an X-radiographic label, a spin label and a nuclear magnetic resonance contrast agent label.

142. The method of claim 141, wherein said chromogenic label is selected from the group consisting of diaminobenzidine and 4-hydroxyazo-benzene-2-carboxylic acid.

143. The method of claim 141, wherein said enzyme label is selected from the group consisting of malate dehydrogenase, staphylococcal nuclease, delta-5-steroid isomerase, yeast-alcohol dehydrogenase, alpha-glycerol phosphate dehydrogenase, triose phosphate isomerase, peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, β-galactosidase, ribonuclease, urease, catalase, glucose-6-phosphate dehydrogenase, glucoamylase and acetylcholine esterase.

144. The method of claim 141, wherein said radioisotopic label is selected from the group consisting of 3H, 111In, 125I, 131I, 32P, 35S, 14C, 51Cr, 57To, 58Co, 59Fe, 75Se, 152Eu, 90Y, 67Cu, 217Ci, 211At, 212Pb, 47Sc and 109Pd.

145. The method of claim 141, wherein said non-radioactive isotopic label is selected from the group consisting Of 157Gd, 55Mn, 162Dy, 52Tr, 56Fe, 99mTc and 112In.

146. The method of claim 141, wherein said fluorescent label is selected from the group consisting of a 152Eu label, a fluorescein label, an isothiocyanate label, a rhodamine label, a phycoerythrin label, a phycocyanin label, an allophycocyanin label, a Green Fluorescent Protein (GFP) label, an o-phthaldehyde label and a fluorescamine label.

147. The method of claim 141, wherein said toxic label is selected from the group consisting of a diphtheria toxin label, a ricin label and a cholera toxin label.

148. The method of claim 141, wherein said chemiluminescent label is selected from the group consisting of a luminol label, an isoluminol label, an aromatic acridinium ester label, an imidazole label, an acridmium salt label, an oxalate ester label, a luciferin label, a luciferase label and an aequorin label.

149. The method of claim 141, wherein said X-radiographic label is barium or cesium.

150. The method of claim 141, wherein said spin label is deuterium.

151. The method of claim 141, wherein said nuclear magnetic resonance contrast agent label is selected from the group consisting of Gd, Mn and iron.

152. A method of eliminating αvβ6-positive metastatic tumor cells in a patient, comprising administering to said patient a therapeutically effective amount of one or more ligands that binds to one or more subunits of integrin αvβ<5 on one or more αvβό-positive metastatic tumor cells, wherein the binding of said ligand to said integrin results in the death, chemosensitization or decreased invasiveness of said metastatic tumor cell.

153. The method of claim 152, wherein said tumor cells are from a metastatic carcinoma.

154. The method of claim 153, wherein said carcinoma is an adenocarcinoma.

155. The method of claim 153, wherein said carcinoma is selected from the group consisting of a breast carcinoma, an endometrial carcinoma, a pancreatic carcinoma, a colorectal carcinoma, a lung carcinoma, an ovarian carcinoma, a cervical carcinoma, a prostatic carcinoma, a liver carcinoma, an esophageal carcinoma, a head and neck carcinoma, a stomach carcinoma and a splenic carcinoma.

156. The method of claim 153, wherein said carcinoma is a breast carcinoma.

157. The method of claim 156, wherein said breast carcinoma is an in situ breast carcinoma.

158. The method of claim 157, wherein said in situ breast carcinoma is selected from the group consisting of a ductal carcinoma in situ (DCIS) and a lobular carcinoma in situ (LCIS).

159. The method of claim 153, wherein said carcinoma is an endometrial carcinoma.

160. The method of claim 153, wherein said carcinoma is a pancreatic carcinoma.

161. The method of claim 153, wherein said carcinoma is a colorectal carcinoma.

162. The method of claim 153, wherein said carcinoma is a cervical carcinoma.

163. The method of claim 153, wherein said carcinoma is a lung carcinoma.

164. The method of claim 152, wherein said ligand that binds to an αvβ6 integrin is an antibody or an αvβ6 epitope-binding fragment thereof.

165. The method of claim 164, wherein said antibody is a monoclonal antibody.

166. The method of claim 165, wherein said monoclonal antibody is a chimeric, primatized or humanized monoclonal antibody.

167. The method of claim 165, wherein said monoclonal antibody is selected from the group consisting of 2Al, 2E5, 1A8, 2B10, 2Bl, IGlO, 7G5, 1C5, 8G6, 3G9, 10D5 and CSβ6.

168. The method of claim 165, wherein said monoclonal antibody is 3G9.

169. The method of claim 165, wherein said monoclonal antibody is 8G6.

170. The method of claim 165, wherein said monoclonal antibody is a humanized monoclonal antibody.

171. The method of claim 170, wherein said humanized monoclonal antibody is hu3G9 (BGOOOl 1).

172. The method of claim 170, wherein said humanized monoclonal antibody is hu8G6

173. The method of claim 152, wherein said ligand is conjugated with at least one cytotoxic compound.

174. The method of claim 152, wherein said ligand is administered to said patient in conjunction with the administration to said patient of at least one cytotoxic compound.

175. The method of claim 173 or claim 174, wherein said cytotoxic compound is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, paclitaxel, melphalan, doxorabicin, methotrexate, 5-fluorouracil, etoposide, mechlorethamine, cyclophosphamide, bleomycin, a calicheamicin, a maytansine, a trichothene, CC 1065, diphtheria A chain, Pseudomonas aeruginosa exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, an Aleuritesfordii protein, a dianthin protein, a Phytolaca americana protein, momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, a tricothecene, a ribonuclease, and a deoxyribonuclease.

176. The method of claim 173 or claim 174, wherein said cytotoxic compound is selected from the group consisting of a radioisotope and a prodrug-activating enzyme.

177. The method of claim 176, wherein said radioisotope is selected from the group consisting Of 211At, 131I, 125I, 90Y, 186Re, 188Re, 153Sm, 212Bi,

P, and radioactive isotopes of Lu.

178. The method of claim 176, wherein said prodrug-activating enzyme is selected from the group consisting of alkaline phosphatase, arylsulfatase, cytosine deaminase, a protease, a D-alanylcarboxypeptidase, a carbohydrate-cleaving enzyme, P-lactamase and a penicillin amidase.

179. The method of claim 152, wherein said ligand is administered to said patient in the form of a pharmaceutical composition comprising said ligand and one or more pharmaceutically acceptable carriers or excipients.

180. The method of claim 152 or claim 179, wherein said ligand or composition is administered to said patient via a route selected from the group consisting of oral administration, parenteral administration, intracranial administration, intrapulmonary administration and intranasal administration.

181. The method of claim 180, wherein said ligand or composition is administered to said patient via a parenteral route selected from the group consisting of intramuscular administration, intravenous administration, intraarterial administration and subcutaneous administration.

182. The method of claim 181, wherein said parenteral route comprises administering said ligand or composition to said patient via injection.

183. A method of eliminating residual αvβ6-positive tumor cells from a patient following surgical excision of a tumor from a tissue or organ of said patient, comprising administering to said patient a therapeutically effective amount of one or more ligands that binds to one or more subunits of integrin αvβ6 on one or more residual tumor cells in said tissue or organ, wherein the binding of said ligand to said integrin results in the death, chemosensitivity or decreased invasiveness of said tumor cell.

184. The method of claim 183, wherein said tumor cells are from a metastatic carcinoma.

185. The method of claim 184, wherein said carcinoma is an adenocarcinoma.

186. The method of claim 184, wherein said carcinoma is selected from the group consisting of a breast carcinoma, an endometrial carcinoma, a pancreatic carcinoma, a colorectal carcinoma, a lung carcinoma, an ovarian carcinoma, a cervical carcinoma, a prostatic carcinoma, a liver carcinoma, an esophageal carcinoma, a head and neck carcinoma, a stomach carcinoma and a splenic carcinoma.

187. The method of claim 184, wherein said carcinoma is a breast carcinoma.

188. The method of claim 187, wherein said breast carcinoma is an in situ breast carcinoma.

189. The method of claim 188, wherein said in situ breast carcinoma is selected from the group consisting of a ductal carcinoma in situ (DCIS) and a lobular carcinoma in situ (LCIS).

190. The method of claim 184, wherein said carcinoma is an endometrial carcinoma.

191. The method of claim 184, wherein said carcinoma is a pancreatic carcinoma.

192. The method of claim 184, wherein said carcinoma is a colorectal carcinoma.

193. The method of claim 184, wherein said carcinoma is a cervical carcinoma.

194. The method of claim 184, wherein said carcinoma is a lung carcinoma.

195. The method of claim 183, wherein said ligand that binds to an αvβ6 integrin is an antibody or an αvβ6 epitope-binding fragment thereof.

196. The method of claim 195, wherein said antibody is a monoclonal antibody.

197. The method of claim 196, wherein said monoclonal antibody is a chimeric, primatized or humanized monoclonal antibody.

198. The method of claim 196, wherein said monoclonal antibody is selected from the group consisting of 2Al, 2E5, 1A8, 2B10, 2Bl, IGlO, 7G5, 1C5, 8G6, 3G9, 10D5 and CSβ6.

199. The method of claim 196, wherein said monoclonal antibody is 3G9.

200. The method of claim 196, wherein said monoclonal antibody is 8G6.

201. The method of claim 196, wherein said monoclonal antibody is a humanized monoclonal antibody.

202. The method of claim 201, wherein said humanized monoclonal antibody is hu3G9 (BGOOOl 1).

203. The method of claim 201, wherein said humanized monoclonal antibody is hu8G6

204. The method of claim 183, wherein said ligand is conjugated with at least one cytotoxic compound.

205. The method of claim 183, wherein said ligand is administered to said patient in conjunction with the administration to said patient of at least one cytotoxic compound.

206. The method of claim 204 or claim 205, wherein said cytotoxic compound is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, paclitaxel, melphalan, doxorabicin, methotrexate, 5-fluorouracil, etoposide, mechlorethamine, cyclophosphamide, bleomycin, a calicheamicin, a maytansine, a trichothene, CC 1065, diphtheria A chain, Pseudomonas aeruginosa exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, an Aleuritesfordii protein, a dianthin protein, a Phytolaca americana protein, momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, a tricothecene, a ribonuclease, and a deoxyribonuclease.

207. The method of claim 204 or claim 205, wherein said cytotoxic compound is selected from the group consisting of a radioisotope and a prodrug-activating enzyme.

208. The method of claim 207, wherein said radioisotope is selected from the group consisting Of 211At, 131I, 125I, 90Y, 186Re, 188Re, 153Sm, 212Bi, 32P, and radioactive isotopes of Lu.

209. The method of claim 207, wherein said prodrug-activating enzyme is selected from the group consisting of alkaline phosphatase, arylsulfatase, cytosine deaminase, a protease, a D-alanylcarboxypeptidase, a carbohydrate-cleaving enzyme, P-lactamase and a penicillin amidase.

210. The method of claim 183, wherein said ligand is administered to said patient in the form of a pharmaceutical composition comprising said ligand and one or more pharmaceutically acceptable carriers or excipients.

211. The method of claim 183 or claim 210, wherein said ligand or composition is administered to said patient via a route selected from the group consisting of oral administration, parenteral administration, intracranial administration, intrapulmonary administration and intranasal administration.

212. The method of claim 211, wherein said ligand or composition is administered to said patient via a parenteral route selected from the group consisting of intramuscular administration, intravenous administration, intraarterial administration and subcutaneous administration.

213. The method of claim 212, wherein said parenteral route comprises administering said ligand or composition to said patient via injection.

214. A method of reducing or preventing the progression of a primary pre-metastatic or pre-invasive tumor to a metastatic or invasive tumor in a patient, comprising administering to said patient a therapeutically effective amount of one or more ligands that binds to one or more subunits of integrin αvβ6 on one or more cells in said pre-metastatic or pre-invasive tumor, wherein the binding of said ligand to said integrin results in the reduction or prevention of invasion of cells of said pre-metastatic or pre-invasive cancer into tissue areas surrounding said primary tumor in said patient.

215. The method of claim 214, wherein said pre-metastatic or preinvasive tumor is a carcinoma.

216. The method of claim 215, wherein said carcinoma is an adenocarcinoma.

217. The method of claim 215, wherein said carcinoma is selected from the group consisting of a breast carcinoma, an endometrial carcinoma, a pancreatic carcinoma, a colorectal carcinoma, a lung carcinoma, an ovarian carcinoma, a cervical carcinoma, a prostatic carcinoma, a liver carcinoma, an esophageal carcinoma, a head and neck carcinoma, a stomach carcinoma and a splenic carcinoma.

218. The method of claim 215, wherein said carcinoma is a breast carcinoma.

219. The method of claim 218, wherein said breast carcinoma is an in situ breast carcinoma.

220. The method of claim 219, wherein said in situ breast carcinoma is selected from the group consisting of a ductal carcinoma in situ (DCIS) and a lobular carcinoma in situ (LCIS).

221. The method of claim 215, wherein said carcinoma is an endometrial carcinoma.

222. The method of claim 215, wherein said carcinoma is a pancreatic carcinoma.

223. The method of claim 215, wherein said carcinoma is a colorectal carcinoma.

224. The method of claim 215, wherein said carcinoma is a cervical carcinoma.

225. The method of claim 215, wherein said carcinoma is a lung carcinoma.

226. The method of claim 214, wherein said ligand that binds to an αvβ6 integrin is an antibody or an αvβ6 epitope-binding fragment thereof.

227. The method of claim 226, wherein said antibody is a monoclonal antibody.

228. The method of claim 227, wherein said monoclonal antibody is a chimeric, primatized or humanized monoclonal antibody.

229. The method of claim 227, wherein said monoclonal antibody is selected from the group consisting of 2Al, 2E5, 1A8, 2B10, 2Bl, IGlO, 7G5, 1C5, 8G6, 3G9, 10D5 and CSβ6.

230. The method of claim 227, wherein said monoclonal antibody is 3G9.

231. The method of claim 227, wherein said monoclonal antibody is 8G6.

232. The method of claim 227, wherein said monoclonal antibody is a humanized monoclonal antibody.

233. The method of claim 232, wherein said humanized monoclonal antibody is hu3G9 (BGOOOl 1).

234. The method of claim 232, wherein said humanized monoclonal antibody is hu8G6

235. The method of claim 214, wherein said ligand is conjugated with at least one cytotoxic compound.

236. The method of claim 214, wherein said ligand is administered to said patient in conjunction with the administration to said patient of at least one cytotoxic compound.

237. The method of claim 235 or claim 236, wherein said cytotoxic compound is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, paclitaxel, melphalan, doxorabicin, methotrexate, 5-fluorouracil, etoposide, mechlorethamine, cyclophosphamide, bleomycin, a calicheamicin, a maytansine, a trichothene, CC1065, diphtheria A chain, Pseudomonas aeruginosa exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, an Aleuritesfordii protein, a dianthin protein, a Phytolaca americana protein, momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, a tricothecene, a ribonuclease, and a deoxyribonuclease.

238. The method of claim 235 or claim 236, wherein said cytotoxic compound is selected from the group consisting of a radioisotope and a prodrug-activating enzyme.

239. The method of claim 238, wherein said radioisotope is selected from the group consisting Of 211At, 131I, 125I, 90Y, 186Re, 188Re, 153Sm, 212Bi, 32P, and radioactive isotopes of Lu.

240. The method of claim 238, wherein said prodrug-activating enzyme is selected from the group consisting of alkaline phosphatase, arylsulfatase, cytosine deaminase, a protease, a D-alanylcarboxypeptidase, a carbohydrate-cleaving enzyme, P-lactamase and a penicillin amidase.

241. The method of claim 214, wherein said ligand is administered to said patient in the form of a pharmaceutical composition comprising said ligand and one or more pharmaceutically acceptable carriers or excipients.

242. The method of claim 214 or claim 241, wherein said ligand or composition is administered to said patient via a route selected from the group consisting of oral administration, parenteral administration, intracranial administration, intrapulmonary administration and intranasal administration.

243. The method of claim 242, wherein said ligand or composition is administered to said patient via a parenteral route selected from the group consisting of intramuscular administration, intravenous administration, intraarterial administration and subcutaneous administration.

244. The method of claim 243, wherein said parenteral route comprises administering said ligand or composition to said patient via injection.