Multimodal fluorine-CY3/5/7-DOTA-hapten compositions, diagnostics, fluorescence guided surgery and radioimmunotherapy

Patent metadata

Field	Value
Publication number	US-12533428-B2
Application number	US-202017790079-A
Country	US
Kind code	B2
Filing date	Dec 30, 2020
Priority date	Dec 31, 2019
Publication date	Jan 27, 2026
Grant date	Jan 27, 2026

Abstract

The present disclosure provides compositions and methods for the detection, and treatment of cancer. Specifically, the compositions of the present technology include multimodal fluorine-cyanine-DOTA-hapten compositions that may be complexed with a radioisotope (e.g., 175 Lu). Also disclosed herein are methods of using the fluorine-cyanine-DOTA-hapten compositions of the present technology in diagnostic imaging as well as pretargeted radioimmunotherapy.

First claim

The invention claimed is:

1 . A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein
X 1 , X 2 , X 3 , and X 4 are each independently a lone pair of electrons (i.e. providing an oxygen anion);
X 5 , X 6 , and X 7 are each independently 18 F or 19 F;
Y 1 and Y 2 are each independently O or S;
n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
y is 1, 2, or 3.

2 . The compound of claim 1 , wherein the compound of Formula I is a compound according to Formula IA

or a pharmaceutically acceptable salt thereof, wherein M 1 is 175 Lu 3+ , 77 Lu 3+ , 63 Tm 3+ , 165 Tm 3+ , 166 Tm 3+ , 168 Tm 3+ , 169 Tm 3+ , 170 Tm 3+ , 171 Tm 3+ , 172 Tm 3+ , 173 Tm 3+ , 165 Ho 3+ , 166 Ho 3+ , 167 Ho 3+ , 169 Er 3+ , 171 Er 3+ , 172 Er 3+ , 157 Dy 3+ , 155 Dy 3+ , 152 Dy 3+ , 153 Dy 3+ , 165 Dy 3+ , 166 Dy 3+ , 162 Dy 3+ , 163 Dy 3+ , 141 Pr 3+ , 142 Pr 3+ , 143 Pr 3+ , 145 Pr 3+ , 64 Cu 2+ , 67 Cu 3+ , 45 Sc 3+ , 69 Ga 3+ , 71 Ga 3+ , 86 Y 3+ , 89 Y 3+ , 90 Y 3+ , 113 In 3+ , 115 In 3+ , 139 La 3+ , 136 Ce 3+ , 138 Ce 3+ , 140 Ce 3+ , 142 Ce 3+ , 151 Eu 3+ , 153 Eu 3+ , 159 Tb 3+ , 154 Gd 3+ , 155 Gd 3+ , 156 Gd 3+ , 157 Gd 3+ , 158 Gd 3+ , or 160 Gd 3+ ; or
wherein the compound of Formula I is a compound according to Formula IB or Formula IC

or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 2 , wherein Y 1 and Y 2 each independently are O; or
wherein M 1 is 175Lu 3+ or 177 Lu 3+ .

4 . A complex comprising the compound of claim 1 and a multispecific antibody or antigen binding fragment thereof that recognizes and binds to the compound and an antigen target; or
wherein the multispecific antibody or antigen binding fragment binds to the compound with a K d that is less than or equal to 100 nM-95 nM, 95-90 nM, 90-85 nM, 85-80 nM, 80-75 nM, 75-70 nM, 70-65 nM, 65-60 nM, 60-55 nM, 55-50 nM, 50-45 nM, 45-40 nM, 40-35 nM, 35-30 nM, 30-25 nM, 25-20 nM, 20-15 nM, 15-10 nM, 10-5 nM, 5-1 nM, 1 nM-950 pM, 950 pM-900 pM, 900 pM-850 pM, 850 pM-800 pM, 800 pM-750 pM, 750 pM-700 pM, 700 pM-650 pM, 650 pM-600 pM, 600 pM-550 pM, 550 pM-500 pM, 500 pM-450 pM, 450 pM-400 pM, 400 pM-350 pM, 350 pM-300 pM, 300 pM-250 pM, 250 pM-200 pM, 200 pM-150 pM, 150 pM-100 pM, 100 pM-50 pM, 50 pM-40 pM, 40 pM-30 pM, 30 pM-20 pM, 20 pM-10 pM, 9 pM, 8 pM, 7 pM, 6 pM, 5 pM, 4 pM, 3 pM, 2.5 pM, 2 pM, 1.5 pM, or 1 pM.

5 . The complex of claim 4 , wherein the antigen target is a tumor associated antigen, an immune cell antigen, a neuronal tissue antigen, a cardiac tissue antigen, a vascular tissue antigen, a fungal antigen, a bacterial antigen, or a viral antigen, optionally wherein
the immune cell antigen is selected from the group consisting of CD2, CD3, CD4, CD8, CD14, CD15, CD16, CD19, CD20, CD24, CD25, CD32, CD56, CD64, CD123, TCR gamma/delta, NKp46, KIR, PD-1, PD-L1, and HLA-DR; or the neuronal tissue antigen is a N-methyl-d-aspartate (NMDA) receptor, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, a γ-aminobutyric acid (GABA) receptor, leucine-rich glioma-inactivated protein 1, contactin-associated protein-like 2, a metabotropic glutamate receptor, a glycine receptor, Amyloid beta, a Neurofibrillary tangle, EGFR, EGFRvIII, B7H3, myelin-associated glycoprotein, CD56, and a P/Q-type voltage-gated calcium channel; or the fungal antigen is Aspergillus fumigatus, Aspergillus restrictus Restrictocin, Aspergillus giganteus Alpha-Sarcin, Aspergillus niger Glucose oxidase, Pectolyase Y-23, HSP104, GLC8, thioredoxin reductase, TRX1, TRX2, glutathione reductase, ATP-sulfurylase/MET3, S. cerevisiae SUMO E1, ubiquitin, Aha1, alcohol dehydrogenase, Glutaredoxin 1, or S. cerevisiae Histone H2A; or the viral antigen is present in a virus selected from the group consisting of Adenovirus, Astrovirus, Cytomegalovirus, Feline Immunodeficiency Virus (FIV), Human Cytomegalovirus, Coronavirus, Coxsackie Virus, Dengue Virus, Epstein-Barr Virus, Enterovirus 71 Virus, Ebola Virus, Hantavirus, Hepatitis A Virus, Hepatitis B Virus, Hepatitis C Virus, Hepatitis D Virus, Hepatitis E Virus, Human Immunodeficiency Virus (HIV), Human Metapneumovirus, Human Papillomvirus, Human Rhinovirus, Human herpesvirus-8, Herpes Simplex Virus, Human T-lymphotropic Virus, Influenza Virus, Japanese Encephalitis Virus, Leukemia Virus, Measles Virus, Mumps Virus, Parvovirus, Rabies Virus, Respiratory Syncytial Virus, Rubella Virus, Rotavirus, Tick-Borne Encephalitis Virus, Varicella Zoster Virus, West Nile virus, and Zika virus; or the bacterial antigen is present in bacteria selected from the group consisting of Bacillus, Borrelia, Bordetella pertussis, Campylobacter jejuni, Chlamydophila pneumonia, Chlamydia trachomatis, Clostridium, Corynebacterium diphterie, Escherichia coli, Haemophilus influenzae, Helicobacter pylori, Legionella Pneumophila, Listeria monocytogenes, Mycobacterium, Pseudomonas aeruginosa, Salmonella, Staphylococcus, Streptococcus pneumonia, Treponema pallidum, Yersinia Enterocolitica, Klebsiella pneumonia, Neisseria gonorrhoeae , and Mycoplasma pneumonia , or the cardiac tissue antigen is selected from the group consisting of Oxidized low-density lipoprotein, Cardiac troponin, Creatinine kinase, and CK-MB Myoglobin; or the vascular tissue antigen is selected from the group consisting of C-reactive protein, Interleukin-6, Cellular adhesion molecules, Beta2-microglobulin, Monocyte chemoattractant protein-1, Soluble CD40 ligand, Myeloperoxidase, Neopterin, Osteoprotegerin, Tumor necrosis factor-alpha, Fibrinogen, D-dimer, von Willebrand factor, Tissue plasminogen activator, Plasminogen activator inhibitor, Lipoprotein-associated phospholipase A2, Lipoprotein (a), Glutathione peroxidase 1, 8-iso-prostaglandin F2a, Vitamin C (L-ascorbic acid), Matrix metalloproteinases and their inhibitors, Pregnancy-associated plasma phosphatase, Vascular endothelial growth factor, Flt-1, Angiopoietin, Tie-1, Homocysteine and asymmetric dimethylarginine; or the tumor associated antigen is selected from the group consisting of Poly-sialic acid, GD3, STEAP1, GPA33, HER2/neu, GD2, MAGE-1, MAGE-3, BAGE, GAGE-1, GAGE-2, MUM-1, CDK4, N-acetylglucosaminyltransferase, p15, gp75, beta-catenin, ErbB2, cancer antigen 125 (CA-125), carcinoembryonic antigen (CEA), RAGE, MART (melanoma antigen), MUC-1, MUC-2, MUC-3, MUC-4, MUC-5ac, MUC-16, MUC-17, tyrosinase, Pmel 17 (gp100), GnT-V intron V sequence (N-acetylglucoaminyltransferase V intron V sequence), Prostate cancer psm, PRAME (melanoma antigen), β-catenin, EBNA (Epstein-Barr Virus nuclear antigen) 1-6, p53, lung resistance protein (LRP) Bcl-2, prostate specific antigen (PSA), Ki-67, CEACAM6, colon-specific antigen-p (CSAp), HLA-DR, CD40, CD74, CD138, EGFR, EGFRvIII, EGP-1, EGP-2, VEGF, PIGF, insulin-like growth factor (ILGF), tenascin, platelet-derived growth factor, IL-6, CD20, CD19, PSMA, CD33, CD123, MET, DLL3, DLL4, CD24, Ang-2, HER3, IGF-1R, CD30, TAG-72, SPEAP, CD45, L1-CAM, Lewis Y (Ley) antigen, E-cadherin, V-cadherin, and EpCAM.

6 . A method for detecting solid tumors or determining surgical tissue margins in a subject in need thereof comprising
(a) administering an effective amount of the complex of claim 5 to the subject, wherein the antigen target is a tumor associated antigen and wherein the complex localizes to a solid tumor expressing the tumor associated antige

Assignees

• Memorial Sloan Kettering Cancer Center
• Univ Cornell

Inventors

• Cheung Nai-Kong V
• Larson Steven M
• Cheal Sarah
• Ting Richard
• Kommidi Hari Krishna
• An Feifei
• Santich Brian

Classifications

• C07K2317/31

  multispecific · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• C07K16/44

  against material not provided for elsewhere {, e.g. haptens, metals, DNA, RNA, amino acids} · CPC title

• C07K16/32

  against translation products of oncogenes · CPC title

• C07K16/3084

  against tumour-associated gangliosides · CPC title