Chelating platform for delivery of radionuclides

Patent metadata

Field	Value
Publication number	US-11235076-B2
Application number	US-201716329178-A
Country	US
Kind code	B2
Filing date	Aug 28, 2017
Priority date	Aug 29, 2016
Publication date	Feb 1, 2022
Grant date	Feb 1, 2022

Abstract

Siderocalin-metal chelator combinations that bind metallic radioisotopes used in nuclear medicine with high affinity are described. The high affinity siderocalin-metal chelator combinations include a number of chelator backbone arrangements with functional groups that coordinate with metals. The siderocalin-metal chelator combinations can be used to deliver radionuclides for imaging and therapeutic purposes.

First claim

What is claimed is:

1. A method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition including a structure

wherein:
at least one of R 1 , R 2 , R 3 , R 4 , and R 6 , individually, are selected from the group consisting of a CAM group, a HA group, and a 1,2-HOPO group;
at least another one of R 1 , R 2 , R 3 , R 4 , and R 6 , individually, are selected from the group consisting of H and an alkyl group having from 1 to 10 carbon atoms;
R 6 is selected from the group consisting of (i) H, (ii) an alkyl group having from 1 to 10 carbon atoms, and (iii) an alkyl group having from 1 to 10 carbon atoms and substituted by at least one of SH, NH 2 , or C(═O)OH;
m is from 1 to 6;
n is from 1 to 6;
o is from 1 to 6; and
wherein the composition is bound to a siderocalin and a metal
wherein the siderocalin has
a sequence as set forth in any one of SEQ ID NOs: 1-8, 12-16, or 18-22,
a sequence as set forth in any one of SEQ ID NOs: 1-8, 12-14, 16, 18, or 22, with a threonine to cysteine mutation at position 54 or a serine to cysteine mutation at position 68,
a sequence as set forth in SEQ ID NOs: 15 or 20 with a threonine to cysteine mutation at position 54, or
a sequence as set forth in SEQ ID NO: 19 with a serine to cysteine mutation at position 68,

thereby treating the cancer in the subject in need thereof.

2. The method of claim 1 , wherein the siderocalin is bound to the composition at position 54, position 68, or both position 54 and position 68 of the siderocalin.

3. The method of claim 1 , wherein the metal is a radionuclide.

4. The method of claim 3 , wherein the radionuclide is selected from the group consisting of 225 Ac, 226 Ac, 228 Ac, 105 Ag, 106 mAg, 110 mAg, 111 Ag, 112 Ag, 113 Ag, 239 Am, 240 Am, 242 Am, 244 Am, 37 Ar, 71 As, 72 As, 73 As, 74 As, 76 As, 77 As, 209 At, 210 At, 191 Au, 192 Au, 193 Au, 194 Au, 195 Au, 196 Au, 196 m 2 Au, 198 Au, 198 mAu, 199 Au, 200 mAu, 128 Ba, 131 Ba, 133 mBa, 135 mBa, 140 Ba, 7 Be, 203 Bi, 204 Bi, 205 Bi, 206 Bi, 210 Bi, 212 Bi, 243 Bk, 244 Bk, 245 Bk, 246 Bk, 248 mBk, 250 Bk, 76 Br, 77 Br, 80 mBr, 82 Br, 11 C, 14 C, 45 Ca, 47 Ca, 107 Cd, 115 Cd, 115 mCd, 117 mCd, 132 Ce, 133 mCe, 134 Ce, 135 Ce 137 Ce, 137 mCe, 139 Ce, 141 Ce, 143 Ce, 144 Ce, 246 Cf, 247 Cf, 253 Cf, 254 Cf, 240 Cm, 241 Cm, 242 Cm, 252 Cm, 55 Co, 56 Co, 57 Co, 58 Co, 58 mCo, 60 Co, 48 Cr, 51 Cr, 127 Cs, 129 Cs, 131 Cs, 132 Cs, 136 Cs, 137 Cs, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 153 Dy, 155 Dy, 157 Dy, 159 Dy, 165 Dy, 166 Dy, 160 Er, 161 Er, 165 Er, 169 Er, 171 Er, 172 Er, 250 Es, 251 Es, 253 Es, 254 Es, 254 mEs, 255 Es, 256 mEs, 145 Eu, 146 Eu, 147 Eu, 148 Eu, 149 Eu, 150 mEu, 152 mEu, 156 Eu, 157 Eu, 52 Fe, 59 Fe, 251 Fm, 252 Fm, 253 Fm, 254 Fm, 255 Fm, 257 Fm, 66 Ga, 67 Ga, 68 Ga, 72 Ga, 73 Ga, 146 Gd, 147 Gd, 149 Gd, 151 Gd, 153 Gd, 159 Gd, 68 Ge, 69 Ge, 71 Ge, 77 Ge, 170 Hf, 171 Hf, 173 Hf, 175 Hf, 179 m 2 Hf, 180 mHf, 181 Hf, 184 Hf, 192 Hg, 193 Hg, 193 mHg, 195 Hg, 195 mHg, 197 Hg, 197 mHg, 203 Hg, 160 mHo, 166 Ho, 167 Ho, 123 I, 124 I, 126 I, 130 I, 132 I, 133 I, 135 I, 109 In, 110 In, 111 In, 114 mIn, 115 mIn, 184 Ir, 185 Ir, 186 Ir, 187 Ir, 188 Ir, 189 Ir, 190 Ir, 190 m 2 Ir, 192 Ir, 193 mIr, 194 Ir, 194 m 2 Ir, 195 mIr, 42 K, 43 K, 76 Kr, 79 Kr, 81 mKr, 85 mKr, 132 La, 133 La, 135 La, 140 La, 141 La, 262 Lr, 169 Lu, 170 Lu, 171 Lu, 172 Lu, 174 mLu, 176 mLu, 177 Lu, 177 mLu, 179 Lu, 257 Md, 258 Md, 260 Md, 28 Mg, 52 Mn, 90 Mo, 93 mMo, 99 Mo, 13 N, 24 Na, 90 Nb, 91 mNb, 92 mNb, 95 Nb, 95 mNb, 96 Nb, 138 Nd, 139 mNd, 140 Nd, 147 Nd, 56 Ni, 57 Ni, 66 Ni, 234 Np, 236 mNp, 238 Np, 239 Np, 15 O, 182 Os, 183 Os, 183 mOs, 185 Os, 189 mOs, 191 Os, 191 mOs, 193 Os, 32 P, 33 P, 228 Pa, 229 Pa, 230 Pa, 232 Pa, 233 Pa, 234 Pa, 200 Pb, 201 Pb, 202 mPb, 203 Pb, 209 Pb, 212 Pb, 100 Pd, 101 Pd, 103 Pd, 109 Pd, 111 mPd, 112 Pd, 143 Pm, 148 Pm, 148 mPm, 149 Pm, 151 Pm, 204 Po, 206 Po, 207 Po, 210 Po, 139 Pr, 142 Pr, 143 Pr, 145 Pr, 188 Pt, 189 Pt, 191 Pt, 193 mPt, 195 mPt, 197 Pt, 200 Pt, 202 Pt, 234 Pu, 237 Pu, 243 Pu, 245 Pu, 246 Pu, 247 Pu, 223 Ra, 224 Ra, 225 Ra, 81 Rb, 82 Rb, 82 mRb, 83 Rb, 84 Rb, 86 Rb, 181 Re, 182 Re, 182 mRe, 183 Re, 184 Re, 184 mRe, 186 Re, 188 Re, 189 Re, 190 mRe, 99 Rh, 99 mRh, 100 Rh, 101 mRh, 102 Rh, 103 mRh, 105 Rh, 211 Rn, 222 Rn, 97 Ru, 103 Ru, 105 Ru, 35 S, 118 mSb, 119 Sb, 120 Sb, 120 mSb, 122 Sb, 124 Sb, 126 Sb, 127 Sb, 128 Sb, 129 Sb, 43 Sc, 44 Sc, 44 mSc, 46 Sc, 47 Sc, 48 Sc, 72 Se, 73 Se, 75 Se, 153 Sm, 156 Sm, 110 Sn, 113 Sn, 117 mSn, 119 mSn, 121 Sn, 123 Sn, 125 Sn, 82 Sr, 83 Sr, 85 Sr, 89 Sr, 91 Sr, 173 Ta, 175 Ta, 176 Ta, 177 Ta, 180 Ta, 182 Ta, 183 Ta, 184 Ta, 149 Tb, 150 Tb, 151 Tb, 152 Tb, 153 Tb, 154 Tb, 154 mTb, 154 m 2 Tb, 155 Tb, 156 Tb, 156 mTb, 156 m 2 Tb, 160 Tb, 161 Tb, 94 Tc, 95 Tc, 95 mTc, 96 Tc, 97 mTc, 99 mTc, 118 Te, 119 Te, 119 mTe, 121 Te, 121 mTe, 123 mTe, 125 mTe, 127 Te, 127 mTe, 129 mTe, 131 mTe, 132 Te, 227 Th, 231 Th, 234 Th, 45 Ti, 198 Tl, 199 Tl, 200 Tl, 201 Tl, 202 Tl, 204 Tl, 165 Tm, 166 Tm, 167 Tm, 168 Tm, 170 Tm, 172 Tm, 173 Tm, 230 U, 231 U, 237 U, 240 U, 48 V, 178 W, 181 W, 185 W, 187 W, 188 W, 122 Xe, 125 Xe, 127 Xe, 129 mXe, 131 mXe, 133 Xe, 133 mXe, 135 Xe, 85 mY, 86 Y, 87 Y, 87 mY, 88 Y, 90 Y, 90 mY, 91 Y, 92 Y, 93 Y, 166 Yb, 169 Yb, 175 Yb, 62 Zn, 65 Zn, 69 mZn, 71 mZn, 72 Zn, 86 Zr, 88 Zr, 89 Zr, 95 Zr, and 97 Zr.

5. The method of claim 1 , further comprising obtaining an image after the administering using positron emission tomography (PET), single photon emission computed tomography, radioisotope renography, or scintigraphy.

6. The method of claim 1 , wherein cellular proliferation is reduced in the subject after administering the composition as compared to cellular proliferation in the subject following diagnosis with the cancer but before administering the composition.

7. The method of claim 1 , wherein the cancer is adrenal cancer, bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, carcinoma, cervical cancer, colon cancer, colorectal cancer, corpus uterine cancer, ear, nose and throat (ENT) cancer, endometrial cancer, esophageal cancer, gastrointestinal cancer, head and neck cancer, Hodgkin's disease cancer, intestinal cancer, kidney cancer, larynx cancer, leukemia, liver cancer, lymph node cancer, lymphoma, lung cancer, melanoma, mesothelioma, myeloma, nasopharynx cancer, neuroblastoma, non-Hodgkin's lymphoma, oral cancer, ovarian cancer, pancreatic cancer, penile cancer, pharynx cancer, prostate cancer, rectal cancer, sarcomcancer, seminomcancer, skin cancer, stomach cancer, teratomcancer, testicular cancer, thyroid cancer, uterine cancer, vaginal cancer, and vascular tumor cancer.

8. The method of claim 1 , wherein the structure is:

wherein:
at least one of R 1 , R 3 , R 4 , or R 5 R 1 , R 2 , R 3 , R 4 , and R 5 , individually, are a CAM group, a HA group, or a 1,2-HOPO group;
optionally, another one of R 1 , R 3 , R 4 , or R 5 R 1 , R 2 , R 3 , R 4 , and R 5 , individually, are H or an alkyl group having from 1 to 10 carbon

Assignees

• Hutchinson Fred Cancer Res
• Univ California

Inventors

• Strong Roland K
• Rupert Peter
• Abergel Rebecca J
• Captain Ilya
• Deblonde Gauthier J P

Classifications

• B01D15/34

  Size-selective separation, e.g. size-exclusion chromatography; Gel filtration; Permeation · CPC title

• C07K14/47

  from mammals · CPC title

• C22B60/02

  Obtaining thorium, uranium, or other actinides · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K51/0482 Primary

  chelates from cyclic ligands, e.g. DOTA · CPC title