CA3199259A1 - Her3 radioimmunotherapy for the treatment of solid cancers - Google Patents
Her3 radioimmunotherapy for the treatment of solid cancersInfo
- Publication number
- CA3199259A1 CA3199259A1 CA3199259A CA3199259A CA3199259A1 CA 3199259 A1 CA3199259 A1 CA 3199259A1 CA 3199259 A CA3199259 A CA 3199259A CA 3199259 A CA3199259 A CA 3199259A CA 3199259 A1 CA3199259 A1 CA 3199259A1
- Authority
- CA
- Canada
- Prior art keywords
- her3
- cancer
- targeting agent
- antibody
- seq
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 186
- 239000007787 solid Substances 0.000 title claims abstract description 20
- 238000011282 treatment Methods 0.000 title claims description 53
- 238000011363 radioimmunotherapy Methods 0.000 title 1
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 claims abstract description 411
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 claims abstract description 411
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 366
- 238000000034 method Methods 0.000 claims abstract description 135
- 201000011510 cancer Diseases 0.000 claims abstract description 91
- 239000000203 mixture Substances 0.000 claims abstract description 45
- 229940125666 actinium-225 Drugs 0.000 claims abstract description 32
- OHSVLFRHMCKCQY-NJFSPNSNSA-N lutetium-177 Chemical compound [177Lu] OHSVLFRHMCKCQY-NJFSPNSNSA-N 0.000 claims abstract description 22
- 231100000682 maximum tolerated dose Toxicity 0.000 claims abstract description 8
- 230000008685 targeting Effects 0.000 claims description 310
- 101000868279 Homo sapiens Leukocyte surface antigen CD47 Proteins 0.000 claims description 115
- 102100032913 Leukocyte surface antigen CD47 Human genes 0.000 claims description 112
- 238000002560 therapeutic procedure Methods 0.000 claims description 61
- 108090000623 proteins and genes Proteins 0.000 claims description 59
- 239000003112 inhibitor Substances 0.000 claims description 58
- 102000037982 Immune checkpoint proteins Human genes 0.000 claims description 54
- 108091008036 Immune checkpoint proteins Proteins 0.000 claims description 54
- 102000004169 proteins and genes Human genes 0.000 claims description 51
- -1 186- e Chemical compound 0.000 claims description 44
- 101710089372 Programmed cell death protein 1 Proteins 0.000 claims description 30
- 230000037396 body weight Effects 0.000 claims description 30
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 28
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 27
- 206010006187 Breast cancer Diseases 0.000 claims description 26
- 208000026310 Breast neoplasm Diseases 0.000 claims description 26
- 230000028617 response to DNA damage stimulus Effects 0.000 claims description 23
- 230000001225 therapeutic effect Effects 0.000 claims description 23
- 229940045513 CTLA4 antagonist Drugs 0.000 claims description 22
- 101001008255 Homo sapiens Immunoglobulin kappa variable 1D-8 Proteins 0.000 claims description 19
- 101001047628 Homo sapiens Immunoglobulin kappa variable 2-29 Proteins 0.000 claims description 19
- 101001008321 Homo sapiens Immunoglobulin kappa variable 2D-26 Proteins 0.000 claims description 19
- 101001047619 Homo sapiens Immunoglobulin kappa variable 3-20 Proteins 0.000 claims description 19
- 101001008263 Homo sapiens Immunoglobulin kappa variable 3D-15 Proteins 0.000 claims description 19
- 102100022949 Immunoglobulin kappa variable 2-29 Human genes 0.000 claims description 19
- 102000000872 ATM Human genes 0.000 claims description 18
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 claims description 18
- 101000998953 Homo sapiens Immunoglobulin heavy variable 1-2 Proteins 0.000 claims description 18
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 claims description 18
- 102100036887 Immunoglobulin heavy variable 1-2 Human genes 0.000 claims description 18
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 claims description 18
- 101000785063 Homo sapiens Serine-protein kinase ATM Proteins 0.000 claims description 16
- 239000002738 chelating agent Substances 0.000 claims description 16
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims description 15
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 15
- 239000002246 antineoplastic agent Substances 0.000 claims description 15
- 229940121581 magrolimab Drugs 0.000 claims description 15
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 claims description 14
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 claims description 14
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 claims description 14
- 206010009944 Colon cancer Diseases 0.000 claims description 13
- 206010033128 Ovarian cancer Diseases 0.000 claims description 13
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 claims description 13
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 13
- 229940127089 cytotoxic agent Drugs 0.000 claims description 13
- 206010017758 gastric cancer Diseases 0.000 claims description 13
- 238000003384 imaging method Methods 0.000 claims description 13
- 229950010079 lumretuzumab Drugs 0.000 claims description 13
- 201000011549 stomach cancer Diseases 0.000 claims description 13
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 12
- 229950008834 seribantumab Drugs 0.000 claims description 12
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 claims description 11
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 claims description 11
- 102000013463 Immunoglobulin Light Chains Human genes 0.000 claims description 11
- 108010065825 Immunoglobulin Light Chains Proteins 0.000 claims description 11
- 208000020816 lung neoplasm Diseases 0.000 claims description 11
- 108010074708 B7-H1 Antigen Proteins 0.000 claims description 10
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 10
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 10
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 claims description 10
- 201000005202 lung cancer Diseases 0.000 claims description 9
- 229950010966 patritumab Drugs 0.000 claims description 9
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 claims description 8
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 claims description 8
- 229950002519 elgemtumab Drugs 0.000 claims description 8
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 8
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 8
- 201000002528 pancreatic cancer Diseases 0.000 claims description 8
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 8
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 7
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 7
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 7
- 201000000849 skin cancer Diseases 0.000 claims description 7
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 6
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 6
- 229940126302 TTI-621 Drugs 0.000 claims description 6
- 229940126301 TTI-622 Drugs 0.000 claims description 6
- 229940125052 lemzoparlimab Drugs 0.000 claims description 6
- 206010014733 Endometrial cancer Diseases 0.000 claims description 5
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 206010038389 Renal cancer Diseases 0.000 claims description 5
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 5
- 201000004101 esophageal cancer Diseases 0.000 claims description 5
- 201000010536 head and neck cancer Diseases 0.000 claims description 5
- 201000010982 kidney cancer Diseases 0.000 claims description 5
- 206010003591 Ataxia Diseases 0.000 claims description 4
- 206010005003 Bladder cancer Diseases 0.000 claims description 4
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 4
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 4
- 206010057644 Testis cancer Diseases 0.000 claims description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 4
- 201000010881 cervical cancer Diseases 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 201000003120 testicular cancer Diseases 0.000 claims description 4
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 4
- 229940123066 Polymerase inhibitor Drugs 0.000 claims description 3
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 4
- 102100023990 60S ribosomal protein L17 Human genes 0.000 claims 1
- 108010021064 CTLA-4 Antigen Proteins 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 63
- 229940124597 therapeutic agent Drugs 0.000 abstract description 25
- 210000004027 cell Anatomy 0.000 description 110
- 108091007433 antigens Proteins 0.000 description 51
- 102000036639 antigens Human genes 0.000 description 51
- 239000000427 antigen Substances 0.000 description 50
- 150000001413 amino acids Chemical group 0.000 description 49
- 235000018102 proteins Nutrition 0.000 description 47
- 230000027455 binding Effects 0.000 description 40
- 108090000765 processed proteins & peptides Proteins 0.000 description 34
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 32
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 32
- 150000003384 small molecules Chemical class 0.000 description 32
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 29
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 29
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 25
- 230000014509 gene expression Effects 0.000 description 25
- 230000005855 radiation Effects 0.000 description 25
- 101150036449 SIRPA gene Proteins 0.000 description 24
- 230000000694 effects Effects 0.000 description 21
- 108020004414 DNA Proteins 0.000 description 18
- 230000002829 reductive effect Effects 0.000 description 18
- 239000003446 ligand Substances 0.000 description 17
- FDLYAMZZIXQODN-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC=2C3=CC=CC=C3C(=O)NN=2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FDLYAMZZIXQODN-UHFFFAOYSA-N 0.000 description 16
- 210000000481 breast Anatomy 0.000 description 15
- 208000035475 disorder Diseases 0.000 description 15
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 15
- 102000001301 EGF receptor Human genes 0.000 description 14
- 108060006698 EGF receptor Proteins 0.000 description 14
- 108060003951 Immunoglobulin Proteins 0.000 description 14
- 206010057249 Phagocytosis Diseases 0.000 description 14
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 14
- 230000006870 function Effects 0.000 description 14
- 102000018358 immunoglobulin Human genes 0.000 description 14
- 230000003993 interaction Effects 0.000 description 14
- PCHKPVIQAHNQLW-CQSZACIVSA-N niraparib Chemical compound N1=C2C(C(=O)N)=CC=CC2=CN1C(C=C1)=CC=C1[C@@H]1CCCNC1 PCHKPVIQAHNQLW-CQSZACIVSA-N 0.000 description 14
- 229950011068 niraparib Drugs 0.000 description 14
- 230000008782 phagocytosis Effects 0.000 description 14
- 230000011664 signaling Effects 0.000 description 14
- 229940079593 drug Drugs 0.000 description 13
- 210000001519 tissue Anatomy 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 12
- 230000037361 pathway Effects 0.000 description 12
- 230000008439 repair process Effects 0.000 description 12
- 235000001014 amino acid Nutrition 0.000 description 11
- 229950009645 istiratumab Drugs 0.000 description 11
- 201000001441 melanoma Diseases 0.000 description 11
- 229960000572 olaparib Drugs 0.000 description 11
- 229960000575 trastuzumab Drugs 0.000 description 11
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 10
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 10
- 230000004913 activation Effects 0.000 description 10
- HWGQMRYQVZSGDQ-HZPDHXFCSA-N chembl3137320 Chemical compound CN1N=CN=C1[C@H]([C@H](N1)C=2C=CC(F)=CC=2)C2=NNC(=O)C3=C2C1=CC(F)=C3 HWGQMRYQVZSGDQ-HZPDHXFCSA-N 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
- 239000012634 fragment Substances 0.000 description 10
- 230000005865 ionizing radiation Effects 0.000 description 10
- 238000002372 labelling Methods 0.000 description 10
- 230000035772 mutation Effects 0.000 description 10
- 102000004196 processed proteins & peptides Human genes 0.000 description 10
- 229950004550 talazoparib Drugs 0.000 description 10
- 210000004881 tumor cell Anatomy 0.000 description 10
- 102000004082 Calreticulin Human genes 0.000 description 9
- 108090000549 Calreticulin Proteins 0.000 description 9
- 210000001744 T-lymphocyte Anatomy 0.000 description 9
- 230000000903 blocking effect Effects 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 230000002611 ovarian Effects 0.000 description 9
- 229950004707 rucaparib Drugs 0.000 description 9
- HMABYWSNWIZPAG-UHFFFAOYSA-N rucaparib Chemical compound C1=CC(CNC)=CC=C1C(N1)=C2CCNC(=O)C3=C2C1=CC(F)=C3 HMABYWSNWIZPAG-UHFFFAOYSA-N 0.000 description 9
- 230000004614 tumor growth Effects 0.000 description 9
- 230000005778 DNA damage Effects 0.000 description 8
- 231100000277 DNA damage Toxicity 0.000 description 8
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 description 8
- 102100024834 T-cell immunoreceptor with Ig and ITIM domains Human genes 0.000 description 8
- 238000002725 brachytherapy Methods 0.000 description 8
- 230000007423 decrease Effects 0.000 description 8
- 230000003828 downregulation Effects 0.000 description 8
- 230000002496 gastric effect Effects 0.000 description 8
- 229920001184 polypeptide Polymers 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 description 7
- 101000831007 Homo sapiens T-cell immunoreceptor with Ig and ITIM domains Proteins 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 230000030833 cell death Effects 0.000 description 7
- 230000021615 conjugation Effects 0.000 description 7
- 210000000987 immune system Anatomy 0.000 description 7
- 230000001965 increasing effect Effects 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 210000004072 lung Anatomy 0.000 description 7
- 210000002307 prostate Anatomy 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 206010041823 squamous cell carcinoma Diseases 0.000 description 7
- BKWJAKQVGHWELA-UHFFFAOYSA-N 1-[6-(2-hydroxypropan-2-yl)-2-pyridinyl]-6-[4-(4-methyl-1-piperazinyl)anilino]-2-prop-2-enyl-3-pyrazolo[3,4-d]pyrimidinone Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC=C2C(=O)N(CC=C)N(C=3N=C(C=CC=3)C(C)(C)O)C2=N1 BKWJAKQVGHWELA-UHFFFAOYSA-N 0.000 description 6
- UDOPJKHABYSVIX-UHFFFAOYSA-N 2-[4,7,10-tris(carboxymethyl)-6-[(4-isothiocyanatophenyl)methyl]-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound C1N(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CCN(CC(O)=O)C1CC1=CC=C(N=C=S)C=C1 UDOPJKHABYSVIX-UHFFFAOYSA-N 0.000 description 6
- 102000036365 BRCA1 Human genes 0.000 description 6
- 230000033616 DNA repair Effects 0.000 description 6
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 6
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 description 6
- 241001436793 Meru Species 0.000 description 6
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 6
- 229950009557 adavosertib Drugs 0.000 description 6
- 238000011374 additional therapy Methods 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 230000009920 chelation Effects 0.000 description 6
- 230000034431 double-strand break repair via homologous recombination Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000002710 external beam radiation therapy Methods 0.000 description 6
- 108020001507 fusion proteins Proteins 0.000 description 6
- 102000037865 fusion proteins Human genes 0.000 description 6
- 230000028993 immune response Effects 0.000 description 6
- 229940072221 immunoglobulins Drugs 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- 229960005386 ipilimumab Drugs 0.000 description 6
- 230000002062 proliferating effect Effects 0.000 description 6
- 238000013519 translation Methods 0.000 description 6
- 238000012447 xenograft mouse model Methods 0.000 description 6
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 5
- JODKFOVZURLVTG-UHFFFAOYSA-N 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone Chemical compound [O-][N+](=O)C1([N+]([O-])=O)CN(C(=O)CBr)C1 JODKFOVZURLVTG-UHFFFAOYSA-N 0.000 description 5
- 108700020463 BRCA1 Proteins 0.000 description 5
- 101150072950 BRCA1 gene Proteins 0.000 description 5
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 description 5
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 5
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 5
- 108091030071 RNAI Proteins 0.000 description 5
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 5
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 5
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 5
- 102100032101 Tumor necrosis factor ligand superfamily member 9 Human genes 0.000 description 5
- 229940041181 antineoplastic drug Drugs 0.000 description 5
- 238000013459 approach Methods 0.000 description 5
- 230000001588 bifunctional effect Effects 0.000 description 5
- 239000002981 blocking agent Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 231100000433 cytotoxic Toxicity 0.000 description 5
- 230000001472 cytotoxic effect Effects 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 238000006471 dimerization reaction Methods 0.000 description 5
- 238000000684 flow cytometry Methods 0.000 description 5
- 229960002949 fluorouracil Drugs 0.000 description 5
- 230000009368 gene silencing by RNA Effects 0.000 description 5
- 230000001976 improved effect Effects 0.000 description 5
- 238000001802 infusion Methods 0.000 description 5
- 231100000225 lethality Toxicity 0.000 description 5
- 229940100352 lynparza Drugs 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 210000004897 n-terminal region Anatomy 0.000 description 5
- 229960003301 nivolumab Drugs 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000001959 radiotherapy Methods 0.000 description 5
- 230000010076 replication Effects 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 231100000402 unacceptable toxicity Toxicity 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 description 4
- 241000272878 Apodiformes Species 0.000 description 4
- 108091007743 BRCA1/2 Proteins 0.000 description 4
- 102100024263 CD160 antigen Human genes 0.000 description 4
- 102100027207 CD27 antigen Human genes 0.000 description 4
- 102100038078 CD276 antigen Human genes 0.000 description 4
- 102000053602 DNA Human genes 0.000 description 4
- 206010061818 Disease progression Diseases 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 description 4
- 101000761938 Homo sapiens CD160 antigen Proteins 0.000 description 4
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 4
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 description 4
- 101001010819 Homo sapiens Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 4
- 101000864057 Homo sapiens Serine/threonine-protein kinase SMG1 Proteins 0.000 description 4
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 4
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 4
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 description 4
- 102100029938 Serine/threonine-protein kinase SMG1 Human genes 0.000 description 4
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 4
- 102100033579 Trophoblast glycoprotein Human genes 0.000 description 4
- 208000035896 Twin-reversed arterial perfusion sequence Diseases 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- QQINRWTZWGJFDB-YPZZEJLDSA-N actinium-225 Chemical compound [225Ac] QQINRWTZWGJFDB-YPZZEJLDSA-N 0.000 description 4
- 230000003213 activating effect Effects 0.000 description 4
- 230000000692 anti-sense effect Effects 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 238000001574 biopsy Methods 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 229960005395 cetuximab Drugs 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
- 201000010989 colorectal carcinoma Diseases 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 230000005750 disease progression Effects 0.000 description 4
- 239000012636 effector Substances 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 102000057750 human ERBB3 Human genes 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 210000004985 myeloid-derived suppressor cell Anatomy 0.000 description 4
- 229960002621 pembrolizumab Drugs 0.000 description 4
- 229960003330 pentetic acid Drugs 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000003439 radiotherapeutic effect Effects 0.000 description 4
- 230000035945 sensitivity Effects 0.000 description 4
- 238000009097 single-agent therapy Methods 0.000 description 4
- 238000002603 single-photon emission computed tomography Methods 0.000 description 4
- 230000004936 stimulating effect Effects 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 229960004964 temozolomide Drugs 0.000 description 4
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 4
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102100038077 CD226 antigen Human genes 0.000 description 3
- 101710185679 CD276 antigen Proteins 0.000 description 3
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- RTZKSTLPRTWFEV-OLZOCXBDSA-N Deoxygomisin A Chemical compound COC1=C2C=3C(OC)=C(OC)C(OC)=CC=3C[C@@H](C)[C@@H](C)CC2=CC2=C1OCO2 RTZKSTLPRTWFEV-OLZOCXBDSA-N 0.000 description 3
- 101150029707 ERBB2 gene Proteins 0.000 description 3
- 102100030013 Endoribonuclease Human genes 0.000 description 3
- 101710199605 Endoribonuclease Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LRULVYSBRWUVGR-FCHUYYIVSA-N GSK2879552 Chemical compound C1=CC(C(=O)O)=CC=C1CN1CCC(CN[C@H]2[C@@H](C2)C=2C=CC=CC=2)CC1 LRULVYSBRWUVGR-FCHUYYIVSA-N 0.000 description 3
- 101000884298 Homo sapiens CD226 antigen Proteins 0.000 description 3
- 101000638251 Homo sapiens Tumor necrosis factor ligand superfamily member 9 Proteins 0.000 description 3
- RTZKSTLPRTWFEV-UHFFFAOYSA-N Isokadsuranin Natural products COC1=C2C=3C(OC)=C(OC)C(OC)=CC=3CC(C)C(C)CC2=CC2=C1OCO2 RTZKSTLPRTWFEV-UHFFFAOYSA-N 0.000 description 3
- 102000017578 LAG3 Human genes 0.000 description 3
- 101150030213 Lag3 gene Proteins 0.000 description 3
- 108010061593 Member 14 Tumor Necrosis Factor Receptors Proteins 0.000 description 3
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 3
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 3
- 229930012538 Paclitaxel Natural products 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 101710113029 Serine/threonine-protein kinase Proteins 0.000 description 3
- 108020004682 Single-Stranded DNA Proteins 0.000 description 3
- 230000006044 T cell activation Effects 0.000 description 3
- 102100028785 Tumor necrosis factor receptor superfamily member 14 Human genes 0.000 description 3
- 108010079206 V-Set Domain-Containing T-Cell Activation Inhibitor 1 Proteins 0.000 description 3
- 102100038929 V-set domain-containing T-cell activation inhibitor 1 Human genes 0.000 description 3
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 210000000612 antigen-presenting cell Anatomy 0.000 description 3
- 229960000074 biopharmaceutical Drugs 0.000 description 3
- OHUHVTCQTUDPIJ-JYCIKRDWSA-N ceralasertib Chemical compound C[C@@H]1COCCN1C1=CC(C2(CC2)[S@](C)(=N)=O)=NC(C=2C=3C=CNC=3N=CC=2)=N1 OHUHVTCQTUDPIJ-JYCIKRDWSA-N 0.000 description 3
- 238000002591 computed tomography Methods 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 3
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 102000044459 human CD47 Human genes 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- APFVFJFRJDLVQX-AHCXROLUSA-N indium-111 Chemical compound [111In] APFVFJFRJDLVQX-AHCXROLUSA-N 0.000 description 3
- 108091008042 inhibitory receptors Proteins 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 230000001394 metastastic effect Effects 0.000 description 3
- 206010061289 metastatic neoplasm Diseases 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 210000001539 phagocyte Anatomy 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000000163 radioactive labelling Methods 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 208000017572 squamous cell neoplasm Diseases 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000002459 sustained effect Effects 0.000 description 3
- 229960001603 tamoxifen Drugs 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 3
- QDLHCMPXEPAAMD-UHFFFAOYSA-N wortmannin Natural products COCC1OC(=O)C2=COC(C3=O)=C2C1(C)C1=C3C2CCC(=O)C2(C)CC1OC(C)=O QDLHCMPXEPAAMD-UHFFFAOYSA-N 0.000 description 3
- QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 description 3
- 229950007155 zenocutuzumab Drugs 0.000 description 3
- IGLYMJRIWWIQQE-QUOODJBBSA-N (1S,2R)-2-phenylcyclopropan-1-amine (1R,2S)-2-phenylcyclopropan-1-amine Chemical compound N[C@H]1C[C@@H]1C1=CC=CC=C1.N[C@@H]1C[C@H]1C1=CC=CC=C1 IGLYMJRIWWIQQE-QUOODJBBSA-N 0.000 description 2
- FQIHLPGWBOBPSG-UHFFFAOYSA-N 2-[4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetamide Chemical compound NC(=O)CN1CCN(CC(N)=O)CCN(CC(N)=O)CCN(CC(N)=O)CC1 FQIHLPGWBOBPSG-UHFFFAOYSA-N 0.000 description 2
- HHLZCENAOIROSL-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound OC(=O)CN1CCNCCN(CC(O)=O)CCN(CC(O)=O)CC1 HHLZCENAOIROSL-UHFFFAOYSA-N 0.000 description 2
- JHALWMSZGCVVEM-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl]acetic acid Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CC1 JHALWMSZGCVVEM-UHFFFAOYSA-N 0.000 description 2
- DROLGCKUCMGNSF-UHFFFAOYSA-N 3,3-dinitroazetidine Chemical compound [O-][N+](=O)C1([N+]([O-])=O)CNC1 DROLGCKUCMGNSF-UHFFFAOYSA-N 0.000 description 2
- 108010082808 4-1BB Ligand Proteins 0.000 description 2
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 2
- 229940125979 ALX148 Drugs 0.000 description 2
- 108700001691 ALX148 Proteins 0.000 description 2
- 206010052747 Adenocarcinoma pancreas Diseases 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020005544 Antisense RNA Proteins 0.000 description 2
- 108091023037 Aptamer Proteins 0.000 description 2
- 206010003594 Ataxia telangiectasia Diseases 0.000 description 2
- 101150065175 Atm gene Proteins 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102000006942 B-Cell Maturation Antigen Human genes 0.000 description 2
- 108010008014 B-Cell Maturation Antigen Proteins 0.000 description 2
- 229940127277 BI-765063 Drugs 0.000 description 2
- 108700040618 BRCA1 Genes Proteins 0.000 description 2
- 108700020462 BRCA2 Proteins 0.000 description 2
- 102000052609 BRCA2 Human genes 0.000 description 2
- 108700010154 BRCA2 Genes Proteins 0.000 description 2
- 101150008921 Brca2 gene Proteins 0.000 description 2
- 241000288950 Callithrix jacchus Species 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- 102100032857 Cyclin-dependent kinase 1 Human genes 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 2
- 239000012623 DNA damaging agent Substances 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- 102100038083 Endosialin Human genes 0.000 description 2
- 108091006020 Fc-tagged proteins Proteins 0.000 description 2
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 2
- 102000010451 Folate receptor alpha Human genes 0.000 description 2
- 108050001931 Folate receptor alpha Proteins 0.000 description 2
- 229940126656 GS-4224 Drugs 0.000 description 2
- 208000031448 Genomic Instability Diseases 0.000 description 2
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 description 2
- 108090000353 Histone deacetylase Proteins 0.000 description 2
- 102000003964 Histone deacetylase Human genes 0.000 description 2
- 101000884275 Homo sapiens Endosialin Proteins 0.000 description 2
- 101000608769 Homo sapiens Galectin-8 Proteins 0.000 description 2
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 description 2
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 description 2
- 101001005719 Homo sapiens Melanoma-associated antigen 3 Proteins 0.000 description 2
- 101001113440 Homo sapiens Poly [ADP-ribose] polymerase 2 Proteins 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 2
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 2
- 102100025082 Melanoma-associated antigen 3 Human genes 0.000 description 2
- 102000029749 Microtubule Human genes 0.000 description 2
- 108091022875 Microtubule Proteins 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- KQKBMHGOHXOHTD-KKUQBAQOSA-N N-[(2S)-5-[[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino]-1-(4-methylpiperazin-1-yl)-1-oxopentan-2-yl]-4-(triazol-1-yl)benzamide Chemical compound FC1=CC=C(C=C1)[C@H]1[C@@H](C1)NCCC[C@@H](C(=O)N1CCN(CC1)C)NC(C1=CC=C(C=C1)N1N=NC=C1)=O KQKBMHGOHXOHTD-KKUQBAQOSA-N 0.000 description 2
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 description 2
- 102000014413 Neuregulin Human genes 0.000 description 2
- 108050003475 Neuregulin Proteins 0.000 description 2
- 102400000058 Neuregulin-1 Human genes 0.000 description 2
- 108090000556 Neuregulin-1 Proteins 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- 238000012879 PET imaging Methods 0.000 description 2
- 102000038030 PI3Ks Human genes 0.000 description 2
- 108091007960 PI3Ks Proteins 0.000 description 2
- 241000282577 Pan troglodytes Species 0.000 description 2
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 2
- 101710164680 Platelet-derived growth factor receptor beta Proteins 0.000 description 2
- 102100023652 Poly [ADP-ribose] polymerase 2 Human genes 0.000 description 2
- 108091026813 Poly(ADPribose) Proteins 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 108020004459 Small interfering RNA Proteins 0.000 description 2
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 2
- 108091008874 T cell receptors Proteins 0.000 description 2
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 2
- JVHROZDXPAUZFK-UHFFFAOYSA-N TETA Chemical compound OC(=O)CN1CCCN(CC(O)=O)CCN(CC(O)=O)CCCN(CC(O)=O)CC1 JVHROZDXPAUZFK-UHFFFAOYSA-N 0.000 description 2
- 102000002259 TNF-Related Apoptosis-Inducing Ligand Receptors Human genes 0.000 description 2
- 108010000449 TNF-Related Apoptosis-Inducing Ligand Receptors Proteins 0.000 description 2
- 101150117918 Tacstd2 gene Proteins 0.000 description 2
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 2
- 102100040112 Tumor necrosis factor receptor superfamily member 10B Human genes 0.000 description 2
- 102100027212 Tumor-associated calcium signal transducer 2 Human genes 0.000 description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 description 2
- 229940122803 Vinca alkaloid Drugs 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 2
- 229960003437 aminoglutethimide Drugs 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940049595 antibody-drug conjugate Drugs 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000008228 bacteriostatic water for injection Substances 0.000 description 2
- 229940062815 barecetamab Drugs 0.000 description 2
- 230000033590 base-excision repair Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 230000000973 chemotherapeutic effect Effects 0.000 description 2
- 239000003184 complementary RNA Substances 0.000 description 2
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 210000004443 dendritic cell Anatomy 0.000 description 2
- 230000000779 depleting effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 230000005782 double-strand break Effects 0.000 description 2
- 229950009791 durvalumab Drugs 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- HESCAJZNRMSMJG-HGYUPSKWSA-N epothilone A Natural products O=C1[C@H](C)[C@H](O)[C@H](C)CCC[C@H]2O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C HESCAJZNRMSMJG-HGYUPSKWSA-N 0.000 description 2
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 description 2
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 210000004602 germ cell Anatomy 0.000 description 2
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 2
- 230000003862 health status Effects 0.000 description 2
- 230000002489 hematologic effect Effects 0.000 description 2
- 230000002519 immonomodulatory effect Effects 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 230000008105 immune reaction Effects 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 229940125721 immunosuppressive agent Drugs 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 229950002950 lintuzumab Drugs 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 238000002595 magnetic resonance imaging Methods 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 208000026037 malignant tumor of neck Diseases 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 210000004688 microtubule Anatomy 0.000 description 2
- 230000033607 mismatch repair Effects 0.000 description 2
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 2
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- 230000000683 nonmetastatic effect Effects 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229960002340 pentostatin Drugs 0.000 description 2
- 229960002087 pertuzumab Drugs 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229960003171 plicamycin Drugs 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002534 radiation-sensitizing agent Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 230000007781 signaling event Effects 0.000 description 2
- 239000004055 small Interfering RNA Substances 0.000 description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000008093 supporting effect Effects 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 229960003741 tranylcypromine Drugs 0.000 description 2
- 238000011277 treatment modality Methods 0.000 description 2
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 2
- 230000003827 upregulation Effects 0.000 description 2
- 206010046766 uterine cancer Diseases 0.000 description 2
- XBBRLCXCBCZIOI-DLBZAZTESA-N vafidemstat Chemical compound O1C(N)=NN=C1CN[C@H]1[C@H](C=2C=CC(OCC=3C=CC=CC=3)=CC=2)C1 XBBRLCXCBCZIOI-DLBZAZTESA-N 0.000 description 2
- 229950011257 veliparib Drugs 0.000 description 2
- JNAHVYVRKWKWKQ-CYBMUJFWSA-N veliparib Chemical compound N=1C2=CC=CC(C(N)=O)=C2NC=1[C@@]1(C)CCCN1 JNAHVYVRKWKWKQ-CYBMUJFWSA-N 0.000 description 2
- 229960003048 vinblastine Drugs 0.000 description 2
- 229960004528 vincristine Drugs 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- 229960002066 vinorelbine Drugs 0.000 description 2
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 2
- 229960000237 vorinostat Drugs 0.000 description 2
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- FCCNKYGSMOSYPV-DEDISHTHSA-N (-)-Epothilone E Natural products O=C1[C@H](C)[C@H](O)[C@@H](C)CCC[C@H]2O[C@H]2C[C@@H](/C(=C\c2nc(CO)sc2)/C)OC(=O)C[C@H](O)C1(C)C FCCNKYGSMOSYPV-DEDISHTHSA-N 0.000 description 1
- UKIMCRYGLFQEOE-RLHMMOOASA-N (-)-Epothilone F Natural products O=C1[C@H](C)[C@H](O)[C@@H](C)CCC[C@@]2(C)O[C@H]2C[C@@H](/C(=C\c2nc(CO)sc2)/C)OC(=O)C[C@H](O)C1(C)C UKIMCRYGLFQEOE-RLHMMOOASA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- RMMFBFFGGLOIKT-UHFFFAOYSA-N 1,2,5,8-tetrazecane Chemical compound C1CNCCNNCCN1 RMMFBFFGGLOIKT-UHFFFAOYSA-N 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- OXHOPZLBSSTTBU-UHFFFAOYSA-N 1,3-bis(bromomethyl)benzene Chemical compound BrCC1=CC=CC(CBr)=C1 OXHOPZLBSSTTBU-UHFFFAOYSA-N 0.000 description 1
- ITWBWJFEJCHKSN-UHFFFAOYSA-N 1,4,7-triazonane Chemical compound C1CNCCNCCN1 ITWBWJFEJCHKSN-UHFFFAOYSA-N 0.000 description 1
- WBPWDDPSYSUQJA-VQTJNVASSA-N 1-[[4-(methoxymethyl)-4-[[[(1R,2S)-2-phenylcyclopropyl]amino]methyl]piperidin-1-yl]methyl]cyclobutane-1-carboxylic acid Chemical compound COCC1(CCN(CC1)CC1(CCC1)C(=O)O)CN[C@H]1[C@@H](C1)C1=CC=CC=C1 WBPWDDPSYSUQJA-VQTJNVASSA-N 0.000 description 1
- 102100025573 1-alkyl-2-acetylglycerophosphocholine esterase Human genes 0.000 description 1
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 1
- APXRHPDHORGIEB-UHFFFAOYSA-N 1H-pyrazolo[4,3-d]pyrimidine Chemical compound N1=CN=C2C=NNC2=C1 APXRHPDHORGIEB-UHFFFAOYSA-N 0.000 description 1
- NPFXDGLJVJSQDY-UHFFFAOYSA-N 2-[2-[carboxymethyl-[(2-hydroxy-5-sulfophenyl)methyl]amino]ethyl-[(2-hydroxy-5-sulfophenyl)methyl]amino]acetic acid Chemical compound C=1C(S(O)(=O)=O)=CC=C(O)C=1CN(CC(=O)O)CCN(CC(O)=O)CC1=CC(S(O)(=O)=O)=CC=C1O NPFXDGLJVJSQDY-UHFFFAOYSA-N 0.000 description 1
- GRUVVLWKPGIYEG-UHFFFAOYSA-N 2-[2-[carboxymethyl-[(2-hydroxyphenyl)methyl]amino]ethyl-[(2-hydroxyphenyl)methyl]amino]acetic acid Chemical compound C=1C=CC=C(O)C=1CN(CC(=O)O)CCN(CC(O)=O)CC1=CC=CC=C1O GRUVVLWKPGIYEG-UHFFFAOYSA-N 0.000 description 1
- FDSYTWVNUJTPMA-UHFFFAOYSA-N 2-[3,9-bis(carboxymethyl)-3,6,9,15-tetrazabicyclo[9.3.1]pentadeca-1(15),11,13-trien-6-yl]acetic acid Chemical compound C1N(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC2=CC=CC1=N2 FDSYTWVNUJTPMA-UHFFFAOYSA-N 0.000 description 1
- WBRUPBYQJCBBBL-UHFFFAOYSA-N 2-[4-(carboxymethyl)-1,4,7-triazonan-1-yl]acetic acid Chemical compound OC(=O)CN1CCNCCN(CC(O)=O)CC1 WBRUPBYQJCBBBL-UHFFFAOYSA-N 0.000 description 1
- SYFGLWDDLZQFNI-UHFFFAOYSA-N 2-[4-(carboxymethyl)-1,4,8,11-tetrazabicyclo[6.6.2]hexadecan-11-yl]acetic acid Chemical compound C1CN(CC(O)=O)CCCN2CCN(CC(=O)O)CCCN1CC2 SYFGLWDDLZQFNI-UHFFFAOYSA-N 0.000 description 1
- GTACSIONMHMRPD-UHFFFAOYSA-N 2-[4-[2-(benzenesulfonamido)ethylsulfanyl]-2,6-difluorophenoxy]acetamide Chemical compound C1=C(F)C(OCC(=O)N)=C(F)C=C1SCCNS(=O)(=O)C1=CC=CC=C1 GTACSIONMHMRPD-UHFFFAOYSA-N 0.000 description 1
- CTRPRMNBTVRDFH-UHFFFAOYSA-N 2-n-methyl-1,3,5-triazine-2,4,6-triamine Chemical compound CNC1=NC(N)=NC(N)=N1 CTRPRMNBTVRDFH-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- UQQQAKFVWNQYTP-UHFFFAOYSA-N 3,6,10,13,16,19-hexazabicyclo[6.6.6]icosane-1,8-diamine Chemical compound C1NCCNCC2(N)CNCCNCC1(N)CNCCNC2 UQQQAKFVWNQYTP-UHFFFAOYSA-N 0.000 description 1
- LKKMLIBUAXYLOY-UHFFFAOYSA-N 3-Amino-1-methyl-5H-pyrido[4,3-b]indole Chemical compound N1C2=CC=CC=C2C2=C1C=C(N)N=C2C LKKMLIBUAXYLOY-UHFFFAOYSA-N 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- QXFUBAAEKCHBQY-UHFFFAOYSA-N 3-[hydroxy(methyl)phosphoryl]propanoic acid Chemical compound CP(O)(=O)CCC(O)=O QXFUBAAEKCHBQY-UHFFFAOYSA-N 0.000 description 1
- 238000011455 3D conformal radiation therapy Methods 0.000 description 1
- UCINOBZMLCREGM-RNNUGBGQSA-N 4-n-[(1r,2s)-2-phenylcyclopropyl]cyclohexane-1,4-diamine;dihydrochloride Chemical compound Cl.Cl.C1CC(N)CCC1N[C@H]1[C@H](C=2C=CC=CC=2)C1 UCINOBZMLCREGM-RNNUGBGQSA-N 0.000 description 1
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 description 1
- SOQZMTFJFHDHTP-UHFFFAOYSA-N 6-(ethylaminomethyl)pyridine-2-carboxylic acid Chemical compound CCNCC1=CC=CC(C(O)=O)=N1 SOQZMTFJFHDHTP-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- 102100040079 A-kinase anchor protein 4 Human genes 0.000 description 1
- 101710109924 A-kinase anchor protein 4 Proteins 0.000 description 1
- 102000017918 ADRB3 Human genes 0.000 description 1
- 108060003355 ADRB3 Proteins 0.000 description 1
- 206010069754 Acquired gene mutation Diseases 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 102100026402 Adhesion G protein-coupled receptor E2 Human genes 0.000 description 1
- 102100026423 Adhesion G protein-coupled receptor E5 Human genes 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 102100032187 Androgen receptor Human genes 0.000 description 1
- 101100412459 Arabidopsis thaliana RER3 gene Proteins 0.000 description 1
- 102100024003 Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 1 Human genes 0.000 description 1
- 229940122815 Aromatase inhibitor Drugs 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 102000030431 Asparaginyl endopeptidase Human genes 0.000 description 1
- 101710130081 Aspergillopepsin-1 Proteins 0.000 description 1
- ZKFQEACEUNWPMT-UHFFFAOYSA-N Azelnidipine Chemical compound CC(C)OC(=O)C1=C(C)NC(N)=C(C(=O)OC2CN(C2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZKFQEACEUNWPMT-UHFFFAOYSA-N 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical class C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 101710144268 B- and T-lymphocyte attenuator Proteins 0.000 description 1
- 102100025218 B-cell differentiation antigen CD72 Human genes 0.000 description 1
- 102100038080 B-cell receptor CD22 Human genes 0.000 description 1
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 1
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 1
- 102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 description 1
- 102100027522 Baculoviral IAP repeat-containing protein 7 Human genes 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 102100037086 Bone marrow stromal antigen 2 Human genes 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 241001457926 Brachys Species 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006143 Brain stem glioma Diseases 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 102100026094 C-type lectin domain family 12 member A Human genes 0.000 description 1
- 108700012439 CA9 Proteins 0.000 description 1
- IYSSKWHJCKNPBJ-UHFFFAOYSA-N CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.CCCCCCCCCCCC Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.CCCCCCCCCCCC IYSSKWHJCKNPBJ-UHFFFAOYSA-N 0.000 description 1
- 229940125838 CC-90011 Drugs 0.000 description 1
- 229940124295 CD38 monoclonal antibody Drugs 0.000 description 1
- 108010058905 CD44v6 antigen Proteins 0.000 description 1
- 102100029390 CMRF35-like molecule 1 Human genes 0.000 description 1
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 1
- 102100024423 Carbonic anhydrase 9 Human genes 0.000 description 1
- 108010051152 Carboxylesterase Proteins 0.000 description 1
- 102000013392 Carboxylesterase Human genes 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 101150015280 Cel gene Proteins 0.000 description 1
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 1
- 206010007953 Central nervous system lymphoma Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 101710098119 Chaperonin GroEL 2 Proteins 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- 101710178046 Chorismate synthase 1 Proteins 0.000 description 1
- 102100038449 Claudin-6 Human genes 0.000 description 1
- 102100035167 Coiled-coil domain-containing protein 54 Human genes 0.000 description 1
- 108050006400 Cyclin Proteins 0.000 description 1
- 102000016736 Cyclin Human genes 0.000 description 1
- 102000002427 Cyclin B Human genes 0.000 description 1
- 108010068150 Cyclin B Proteins 0.000 description 1
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 1
- 101710106279 Cyclin-dependent kinase 1 Proteins 0.000 description 1
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 1
- 102100026804 Cyclin-dependent kinase 6 Human genes 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 101710152695 Cysteine synthase 1 Proteins 0.000 description 1
- 102100031007 Cytosolic non-specific dipeptidase Human genes 0.000 description 1
- 230000012746 DNA damage checkpoint Effects 0.000 description 1
- 102100034157 DNA mismatch repair protein Msh2 Human genes 0.000 description 1
- 230000008265 DNA repair mechanism Effects 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 101100481408 Danio rerio tie2 gene Proteins 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- UQBOJOOOTLPNST-UHFFFAOYSA-N Dehydroalanine Chemical compound NC(=C)C(O)=O UQBOJOOOTLPNST-UHFFFAOYSA-N 0.000 description 1
- 101100294331 Drosophila melanogaster nod gene Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000012804 EPCAM Human genes 0.000 description 1
- 101150084967 EPCAM gene Proteins 0.000 description 1
- 108700041152 Endoplasmic Reticulum Chaperone BiP Proteins 0.000 description 1
- 102100021451 Endoplasmic reticulum chaperone BiP Human genes 0.000 description 1
- 108010055196 EphA2 Receptor Proteins 0.000 description 1
- 102100030340 Ephrin type-A receptor 2 Human genes 0.000 description 1
- 102100023721 Ephrin-B2 Human genes 0.000 description 1
- 108010044090 Ephrin-B2 Proteins 0.000 description 1
- QXRSDHAAWVKZLJ-OXZHEXMSSA-N Epothilone B Natural products O=C1[C@H](C)[C@H](O)[C@@H](C)CCC[C@@]2(C)O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C QXRSDHAAWVKZLJ-OXZHEXMSSA-N 0.000 description 1
- BEFZAMRWPCMWFJ-JRBBLYSQSA-N Epothilone C Natural products O=C1[C@H](C)[C@@H](O)[C@@H](C)CCC/C=C\C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C BEFZAMRWPCMWFJ-JRBBLYSQSA-N 0.000 description 1
- XOZIUKBZLSUILX-SDMHVBBESA-N Epothilone D Natural products O=C1[C@H](C)[C@@H](O)[C@@H](C)CCC/C(/C)=C/C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C XOZIUKBZLSUILX-SDMHVBBESA-N 0.000 description 1
- UKIMCRYGLFQEOE-UHFFFAOYSA-N Epothilone F Natural products O1C(=O)CC(O)C(C)(C)C(=O)C(C)C(O)C(C)CCCC2(C)OC2CC1C(C)=CC1=CSC(CO)=N1 UKIMCRYGLFQEOE-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 1
- 102100031507 Fc receptor-like protein 5 Human genes 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 101150032879 Fcrl5 gene Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000010449 Folate receptor beta Human genes 0.000 description 1
- 108050001930 Folate receptor beta Proteins 0.000 description 1
- 108090000123 Fos-related antigen 1 Proteins 0.000 description 1
- 102000003817 Fos-related antigen 1 Human genes 0.000 description 1
- 102100036939 G-protein coupled receptor 20 Human genes 0.000 description 1
- 102100021197 G-protein coupled receptor family C group 5 member D Human genes 0.000 description 1
- 230000010190 G1 phase Effects 0.000 description 1
- 108700011146 GPA 7 Proteins 0.000 description 1
- 102100030708 GTPase KRas Human genes 0.000 description 1
- 102000044445 Galectin-8 Human genes 0.000 description 1
- 102100039554 Galectin-8 Human genes 0.000 description 1
- 101100264215 Gallus gallus XRCC6 gene Proteins 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 102100032530 Glypican-3 Human genes 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 208000017891 HER2 positive breast carcinoma Diseases 0.000 description 1
- 101150112743 HSPA5 gene Proteins 0.000 description 1
- 108010007712 Hepatitis A Virus Cellular Receptor 1 Proteins 0.000 description 1
- 108010007707 Hepatitis A Virus Cellular Receptor 2 Proteins 0.000 description 1
- 102100034459 Hepatitis A virus cellular receptor 1 Human genes 0.000 description 1
- 208000008051 Hereditary Nonpolyposis Colorectal Neoplasms Diseases 0.000 description 1
- 206010051922 Hereditary non-polyposis colorectal cancer syndrome Diseases 0.000 description 1
- 102100034533 Histone H2AX Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000718211 Homo sapiens Adhesion G protein-coupled receptor E2 Proteins 0.000 description 1
- 101000718243 Homo sapiens Adhesion G protein-coupled receptor E5 Proteins 0.000 description 1
- 101000934359 Homo sapiens B-cell differentiation antigen CD72 Proteins 0.000 description 1
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 description 1
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 1
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 1
- 101000936083 Homo sapiens Baculoviral IAP repeat-containing protein 7 Proteins 0.000 description 1
- 101000740785 Homo sapiens Bone marrow stromal antigen 2 Proteins 0.000 description 1
- 101000912622 Homo sapiens C-type lectin domain family 12 member A Proteins 0.000 description 1
- 101000884279 Homo sapiens CD276 antigen Proteins 0.000 description 1
- 101000990055 Homo sapiens CMRF35-like molecule 1 Proteins 0.000 description 1
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 Proteins 0.000 description 1
- 101000914321 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 7 Proteins 0.000 description 1
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 description 1
- 101000882898 Homo sapiens Claudin-6 Proteins 0.000 description 1
- 101000737052 Homo sapiens Coiled-coil domain-containing protein 54 Proteins 0.000 description 1
- 101000868333 Homo sapiens Cyclin-dependent kinase 1 Proteins 0.000 description 1
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 1
- 101001134036 Homo sapiens DNA mismatch repair protein Msh2 Proteins 0.000 description 1
- 101000909198 Homo sapiens DNA polymerase delta catalytic subunit Proteins 0.000 description 1
- 101001137256 Homo sapiens DNA-(apurinic or apyrimidinic site) lyase Proteins 0.000 description 1
- 101000954709 Homo sapiens Doublecortin domain-containing protein 2 Proteins 0.000 description 1
- 101001071355 Homo sapiens G-protein coupled receptor 20 Proteins 0.000 description 1
- 101001040713 Homo sapiens G-protein coupled receptor family C group 5 member D Proteins 0.000 description 1
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 1
- 101001014668 Homo sapiens Glypican-3 Proteins 0.000 description 1
- 101000985516 Homo sapiens Hermansky-Pudlak syndrome 5 protein Proteins 0.000 description 1
- 101001067891 Homo sapiens Histone H2AX Proteins 0.000 description 1
- 101000878602 Homo sapiens Immunoglobulin alpha Fc receptor Proteins 0.000 description 1
- 101001103039 Homo sapiens Inactive tyrosine-protein kinase transmembrane receptor ROR1 Proteins 0.000 description 1
- 101000998120 Homo sapiens Interleukin-3 receptor subunit alpha Proteins 0.000 description 1
- 101000614481 Homo sapiens Kidney-associated antigen 1 Proteins 0.000 description 1
- 101001065550 Homo sapiens Lymphocyte antigen 6K Proteins 0.000 description 1
- 101001018034 Homo sapiens Lymphocyte antigen 75 Proteins 0.000 description 1
- 101001014223 Homo sapiens MAPK/MAK/MRK overlapping kinase Proteins 0.000 description 1
- 101000578784 Homo sapiens Melanoma antigen recognized by T-cells 1 Proteins 0.000 description 1
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 description 1
- 101001051490 Homo sapiens Neural cell adhesion molecule L1 Proteins 0.000 description 1
- 101001103036 Homo sapiens Nuclear receptor ROR-alpha Proteins 0.000 description 1
- 101000613490 Homo sapiens Paired box protein Pax-3 Proteins 0.000 description 1
- 101000601724 Homo sapiens Paired box protein Pax-5 Proteins 0.000 description 1
- 101000589399 Homo sapiens Pannexin-3 Proteins 0.000 description 1
- 101000691463 Homo sapiens Placenta-specific protein 1 Proteins 0.000 description 1
- 101001064779 Homo sapiens Plexin domain-containing protein 2 Proteins 0.000 description 1
- 101000617725 Homo sapiens Pregnancy-specific beta-1-glycoprotein 2 Proteins 0.000 description 1
- 101001109792 Homo sapiens Pro-neuregulin-2, membrane-bound isoform Proteins 0.000 description 1
- 101001136592 Homo sapiens Prostate stem cell antigen Proteins 0.000 description 1
- 101001136981 Homo sapiens Proteasome subunit beta type-9 Proteins 0.000 description 1
- 101000880770 Homo sapiens Protein SSX2 Proteins 0.000 description 1
- 101000999079 Homo sapiens Radiation-inducible immediate-early gene IEX-1 Proteins 0.000 description 1
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 1
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 1
- 101001094545 Homo sapiens Retrotransposon-like protein 1 Proteins 0.000 description 1
- 101000665137 Homo sapiens Scm-like with four MBT domains protein 1 Proteins 0.000 description 1
- 101000777277 Homo sapiens Serine/threonine-protein kinase Chk2 Proteins 0.000 description 1
- 101000884271 Homo sapiens Signal transducer CD24 Proteins 0.000 description 1
- 101000824971 Homo sapiens Sperm surface protein Sp17 Proteins 0.000 description 1
- 101000707569 Homo sapiens Splicing factor 3A subunit 3 Proteins 0.000 description 1
- 101000873927 Homo sapiens Squamous cell carcinoma antigen recognized by T-cells 3 Proteins 0.000 description 1
- 101000874179 Homo sapiens Syndecan-1 Proteins 0.000 description 1
- 101000655352 Homo sapiens Telomerase reverse transcriptase Proteins 0.000 description 1
- 101000772267 Homo sapiens Thyrotropin receptor Proteins 0.000 description 1
- 101000894428 Homo sapiens Transcriptional repressor CTCFL Proteins 0.000 description 1
- 101000638154 Homo sapiens Transmembrane protease serine 2 Proteins 0.000 description 1
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 1
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 1
- 101001047681 Homo sapiens Tyrosine-protein kinase Lck Proteins 0.000 description 1
- 101000808105 Homo sapiens Uroplakin-2 Proteins 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- 101000814512 Homo sapiens X antigen family member 1 Proteins 0.000 description 1
- DOMWKUIIPQCAJU-LJHIYBGHSA-N Hydroxyprogesterone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)CCCCC)[C@@]1(C)CC2 DOMWKUIIPQCAJU-LJHIYBGHSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 108010031794 IGF Type 1 Receptor Proteins 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 102100038005 Immunoglobulin alpha Fc receptor Human genes 0.000 description 1
- 102100039615 Inactive tyrosine-protein kinase transmembrane receptor ROR1 Human genes 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000004553 Interleukin-11 Receptors Human genes 0.000 description 1
- 108010017521 Interleukin-11 Receptors Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 102100033493 Interleukin-3 receptor subunit alpha Human genes 0.000 description 1
- 102100034872 Kallikrein-4 Human genes 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 102100031413 L-dopachrome tautomerase Human genes 0.000 description 1
- 101710093778 L-dopachrome tautomerase Proteins 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- 102100020862 Lymphocyte activation gene 3 protein Human genes 0.000 description 1
- 102100032129 Lymphocyte antigen 6K Human genes 0.000 description 1
- 102100033486 Lymphocyte antigen 75 Human genes 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 201000005027 Lynch syndrome Diseases 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 229940123628 Lysine (K)-specific demethylase 1A inhibitor Drugs 0.000 description 1
- 102100031520 MAPK/MAK/MRK overlapping kinase Human genes 0.000 description 1
- 108010010995 MART-1 Antigen Proteins 0.000 description 1
- 102000016200 MART-1 Antigen Human genes 0.000 description 1
- 229910015837 MSH2 Inorganic materials 0.000 description 1
- 108700012912 MYCN Proteins 0.000 description 1
- 101150022024 MYCN gene Proteins 0.000 description 1
- 241000282567 Macaca fascicularis Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102100022430 Melanocyte protein PMEL Human genes 0.000 description 1
- 102100028389 Melanoma antigen recognized by T-cells 1 Human genes 0.000 description 1
- 102000000440 Melanoma-associated antigen Human genes 0.000 description 1
- 108050008953 Melanoma-associated antigen Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 108090000015 Mesothelin Proteins 0.000 description 1
- 102000003735 Mesothelin Human genes 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 108060004795 Methyltransferase Proteins 0.000 description 1
- 102100034256 Mucin-1 Human genes 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 101100063504 Mus musculus Dlx2 gene Proteins 0.000 description 1
- 101100481410 Mus musculus Tek gene Proteins 0.000 description 1
- 108700026495 N-Myc Proto-Oncogene Proteins 0.000 description 1
- MVSQDUZRRVBYLA-HYARGMPZSA-N N-[(E)-1-(5-chloro-2-hydroxyphenyl)ethylideneamino]-3-(4-methylpiperazin-1-yl)sulfonylbenzamide Chemical compound C1CN(C)CCN1S(=O)(=O)C1=CC=CC(C(=O)N\N=C(/C)C=2C(=CC=C(Cl)C=2)O)=C1 MVSQDUZRRVBYLA-HYARGMPZSA-N 0.000 description 1
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 1
- NCNRHFGMJRPRSK-UHFFFAOYSA-N N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]-2-propenamide Chemical compound ONC(=O)C=CC1=CC=CC(S(=O)(=O)NC=2C=CC=CC=2)=C1 NCNRHFGMJRPRSK-UHFFFAOYSA-N 0.000 description 1
- 102100030124 N-myc proto-oncogene protein Human genes 0.000 description 1
- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 description 1
- 241001181114 Neta Species 0.000 description 1
- 108010069196 Neural Cell Adhesion Molecules Proteins 0.000 description 1
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 description 1
- 102100024964 Neural cell adhesion molecule L1 Human genes 0.000 description 1
- 102000048238 Neuregulin-1 Human genes 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 239000012661 PARP inhibitor Substances 0.000 description 1
- 102100040891 Paired box protein Pax-3 Human genes 0.000 description 1
- 102100037504 Paired box protein Pax-5 Human genes 0.000 description 1
- 102100032364 Pannexin-3 Human genes 0.000 description 1
- 208000000821 Parathyroid Neoplasms Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 1
- 201000005746 Pituitary adenoma Diseases 0.000 description 1
- 206010061538 Pituitary tumour benign Diseases 0.000 description 1
- 102100026181 Placenta-specific protein 1 Human genes 0.000 description 1
- 206010035603 Pleural mesothelioma Diseases 0.000 description 1
- 102100031889 Plexin domain-containing protein 2 Human genes 0.000 description 1
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 1
- 208000006994 Precancerous Conditions Diseases 0.000 description 1
- 102100022019 Pregnancy-specific beta-1-glycoprotein 2 Human genes 0.000 description 1
- 102100022668 Pro-neuregulin-2, membrane-bound isoform Human genes 0.000 description 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 1
- 102100036735 Prostate stem cell antigen Human genes 0.000 description 1
- 102100035764 Proteasome subunit beta type-9 Human genes 0.000 description 1
- 102100032831 Protein ITPRID2 Human genes 0.000 description 1
- 102100037686 Protein SSX2 Human genes 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 208000019155 Radiation injury Diseases 0.000 description 1
- 102100036900 Radiation-inducible immediate-early gene IEX-1 Human genes 0.000 description 1
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102300033259 Receptor tyrosine-protein kinase erbB-3 isoform 1 Human genes 0.000 description 1
- 102100029981 Receptor tyrosine-protein kinase erbB-4 Human genes 0.000 description 1
- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 1
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 1
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 101100111629 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) KAR2 gene Proteins 0.000 description 1
- 102100031075 Serine/threonine-protein kinase Chk2 Human genes 0.000 description 1
- 101710173694 Short transient receptor potential channel 2 Proteins 0.000 description 1
- 102100038081 Signal transducer CD24 Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 102100037253 Solute carrier family 45 member 3 Human genes 0.000 description 1
- 102100031710 Splicing factor 3A subunit 3 Human genes 0.000 description 1
- 102100035748 Squamous cell carcinoma antigen recognized by T-cells 3 Human genes 0.000 description 1
- 208000036765 Squamous cell carcinoma of the esophagus Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 101800001271 Surface protein Proteins 0.000 description 1
- 108010002687 Survivin Proteins 0.000 description 1
- 102100035721 Syndecan-1 Human genes 0.000 description 1
- 230000020385 T cell costimulation Effects 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 101710090983 T-cell immunoreceptor with Ig and ITIM domains Proteins 0.000 description 1
- 101150057140 TACSTD1 gene Proteins 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 108010017842 Telomerase Proteins 0.000 description 1
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 102100029337 Thyrotropin receptor Human genes 0.000 description 1
- 102100021393 Transcriptional repressor CTCFL Human genes 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
- 102100031989 Transmembrane protease serine 2 Human genes 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 101710190034 Trophoblast glycoprotein Proteins 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 1
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 1
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 1
- 102000003425 Tyrosinase Human genes 0.000 description 1
- 108060008724 Tyrosinase Proteins 0.000 description 1
- 102100024036 Tyrosine-protein kinase Lck Human genes 0.000 description 1
- 101150114976 US21 gene Proteins 0.000 description 1
- 208000023915 Ureteral Neoplasms Diseases 0.000 description 1
- 206010046458 Urethral neoplasms Diseases 0.000 description 1
- 208000006593 Urologic Neoplasms Diseases 0.000 description 1
- 102100038851 Uroplakin-2 Human genes 0.000 description 1
- 201000003761 Vaginal carcinoma Diseases 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 102100039490 X antigen family member 1 Human genes 0.000 description 1
- 102000002258 X-ray Repair Cross Complementing Protein 1 Human genes 0.000 description 1
- 108010000443 X-ray Repair Cross Complementing Protein 1 Proteins 0.000 description 1
- 102100036976 X-ray repair cross-complementing protein 6 Human genes 0.000 description 1
- 101100476214 Xenopus laevis runx1 gene Proteins 0.000 description 1
- 201000006083 Xeroderma Pigmentosum Diseases 0.000 description 1
- 101150042435 Xrcc1 gene Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- RCXMQNIDOFXYDO-UHFFFAOYSA-N [4,7,10-tris(phosphonomethyl)-1,4,7,10-tetrazacyclododec-1-yl]methylphosphonic acid Chemical compound OP(O)(=O)CN1CCN(CP(O)(O)=O)CCN(CP(O)(O)=O)CCN(CP(O)(O)=O)CC1 RCXMQNIDOFXYDO-UHFFFAOYSA-N 0.000 description 1
- 229930183665 actinomycin Natural products 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000006786 activation induced cell death Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 230000001780 adrenocortical effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 101150066984 aml gene Proteins 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 108010080146 androgen receptors Proteins 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- RGHILYZRVFRRNK-UHFFFAOYSA-N anthracene-1,2-dione Chemical class C1=CC=C2C=C(C(C(=O)C=C3)=O)C3=CC2=C1 RGHILYZRVFRRNK-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000005911 anti-cytotoxic effect Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000001446 anti-myeloma Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 230000006023 anti-tumor response Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045687 antimetabolites folic acid analogs Drugs 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 230000005975 antitumor immune response Effects 0.000 description 1
- 230000009118 appropriate response Effects 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 239000010425 asbestos Substances 0.000 description 1
- 108010055066 asparaginylendopeptidase Proteins 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 229950004646 azelnidipine Drugs 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 229960003094 belinostat Drugs 0.000 description 1
- NCNRHFGMJRPRSK-MDZDMXLPSA-N belinostat Chemical compound ONC(=O)\C=C\C1=CC=CC(S(=O)(=O)NC=2C=CC=CC=2)=C1 NCNRHFGMJRPRSK-MDZDMXLPSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical class N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 238000011243 body radiation therapy Methods 0.000 description 1
- 229940070292 bomedemstat Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229930195731 calicheamicin Natural products 0.000 description 1
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 description 1
- 125000001314 canonical amino-acid group Chemical group 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000025084 cell cycle arrest Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 208000025997 central nervous system neoplasm Diseases 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- SZMJVTADHFNAIS-BJMVGYQFSA-N chidamide Chemical compound NC1=CC(F)=CC=C1NC(=O)C(C=C1)=CC=C1CNC(=O)\C=C\C1=CC=CN=C1 SZMJVTADHFNAIS-BJMVGYQFSA-N 0.000 description 1
- 208000012191 childhood neoplasm Diseases 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 210000003040 circulating cell Anatomy 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000007398 colorimetric assay Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 238000007596 consolidation process Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000002711 conventional external beam radiation therapy Methods 0.000 description 1
- 238000011443 conventional therapy Methods 0.000 description 1
- 108091008034 costimulatory receptors Proteins 0.000 description 1
- 230000009260 cross reactivity Effects 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 229960002204 daratumumab Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000012649 demethylating agent Substances 0.000 description 1
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 1
- 230000002074 deregulated effect Effects 0.000 description 1
- BEFZAMRWPCMWFJ-UHFFFAOYSA-N desoxyepothilone A Natural products O1C(=O)CC(O)C(C)(C)C(=O)C(C)C(O)C(C)CCCC=CCC1C(C)=CC1=CSC(C)=N1 BEFZAMRWPCMWFJ-UHFFFAOYSA-N 0.000 description 1
- XOZIUKBZLSUILX-UHFFFAOYSA-N desoxyepothilone B Natural products O1C(=O)CC(O)C(C)(C)C(=O)C(C)C(O)C(C)CCCC(C)=CCC1C(C)=CC1=CSC(C)=N1 XOZIUKBZLSUILX-UHFFFAOYSA-N 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 108700013553 diamsar chelate Proteins 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 229960000452 diethylstilbestrol Drugs 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229950009964 drozitumab Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 108010087914 epidermal growth factor receptor VIII Proteins 0.000 description 1
- 230000007608 epigenetic mechanism Effects 0.000 description 1
- 229930013356 epothilone Natural products 0.000 description 1
- QXRSDHAAWVKZLJ-PVYNADRNSA-N epothilone B Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 QXRSDHAAWVKZLJ-PVYNADRNSA-N 0.000 description 1
- BEFZAMRWPCMWFJ-QJKGZULSSA-N epothilone C Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C=C/C[C@H]1C(\C)=C\C1=CSC(C)=N1 BEFZAMRWPCMWFJ-QJKGZULSSA-N 0.000 description 1
- XOZIUKBZLSUILX-GIQCAXHBSA-N epothilone D Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C(\C)=C\C1=CSC(C)=N1 XOZIUKBZLSUILX-GIQCAXHBSA-N 0.000 description 1
- FCCNKYGSMOSYPV-UHFFFAOYSA-N epothilone E Natural products O1C(=O)CC(O)C(C)(C)C(=O)C(C)C(O)C(C)CCCC2OC2CC1C(C)=CC1=CSC(CO)=N1 FCCNKYGSMOSYPV-UHFFFAOYSA-N 0.000 description 1
- FCCNKYGSMOSYPV-OKOHHBBGSA-N epothilone e Chemical compound C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(CO)=N1 FCCNKYGSMOSYPV-OKOHHBBGSA-N 0.000 description 1
- UKIMCRYGLFQEOE-RGJAOAFDSA-N epothilone f Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(CO)=N1 UKIMCRYGLFQEOE-RGJAOAFDSA-N 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 208000007276 esophageal squamous cell carcinoma Diseases 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- ADFOJJHRTBFFOF-RBRWEJTLSA-N estramustine phosphate Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)OP(O)(O)=O)[C@@H]4[C@@H]3CCC2=C1 ADFOJJHRTBFFOF-RBRWEJTLSA-N 0.000 description 1
- 229960004750 estramustine phosphate Drugs 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- IFQUWYZCAGRUJN-UHFFFAOYSA-N ethylenediaminediacetic acid Chemical compound OC(=O)CNCCNCC(O)=O IFQUWYZCAGRUJN-UHFFFAOYSA-N 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 229960005167 everolimus Drugs 0.000 description 1
- 230000006846 excision repair Effects 0.000 description 1
- 201000001343 fallopian tube carcinoma Diseases 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 229960005304 fludarabine phosphate Drugs 0.000 description 1
- 229960001751 fluoxymesterone Drugs 0.000 description 1
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- 125000002446 fucosyl group Chemical group C1([C@@H](O)[C@H](O)[C@H](O)[C@@H](O1)C)* 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229960000578 gemtuzumab Drugs 0.000 description 1
- 229960003297 gemtuzumab ozogamicin Drugs 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical class C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 1
- 230000036433 growing body Effects 0.000 description 1
- 101150028578 grp78 gene Proteins 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 244000144980 herd Species 0.000 description 1
- 238000000097 high energy electron diffraction Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 102000051957 human ERBB2 Human genes 0.000 description 1
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- ALHBJBCQLJZYON-ZQDZILKHSA-N iadademstat Chemical compound C1C[C@@H](N)CC[C@@H]1N[C@H]1[C@H](C=2C=CC=CC=2)C1 ALHBJBCQLJZYON-ZQDZILKHSA-N 0.000 description 1
- 229940121452 iadademstat Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 238000002786 image-guided radiation therapy Methods 0.000 description 1
- 230000005934 immune activation Effects 0.000 description 1
- 230000005746 immune checkpoint blockade Effects 0.000 description 1
- 239000012642 immune effector Substances 0.000 description 1
- 230000008088 immune pathway Effects 0.000 description 1
- 230000008629 immune suppression Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000006028 immune-suppresssive effect Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 210000005008 immunosuppressive cell Anatomy 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 229940055742 indium-111 Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 108091006086 inhibitor proteins Proteins 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000002721 intensity-modulated radiation therapy Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229950007752 isatuximab Drugs 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 108010024383 kallikrein 4 Proteins 0.000 description 1
- 101150085005 ku70 gene Proteins 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 230000004777 loss-of-function mutation Effects 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 241001515942 marmosets Species 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 238000012737 microarray-based gene expression Methods 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 238000012243 multiplex automated genomic engineering Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 210000004296 naive t lymphocyte Anatomy 0.000 description 1
- 229950009793 naptumomab estafenatox Drugs 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229950004847 navitoclax Drugs 0.000 description 1
- JLYAXFNOILIKPP-KXQOOQHDSA-N navitoclax Chemical compound C([C@@H](NC1=CC=C(C=C1S(=O)(=O)C(F)(F)F)S(=O)(=O)NC(=O)C1=CC=C(C=C1)N1CCN(CC1)CC1=C(CCC(C1)(C)C)C=1C=CC(Cl)=CC=1)CSC=1C=CC=CC=1)CN1CCOCC1 JLYAXFNOILIKPP-KXQOOQHDSA-N 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000000626 neurodegenerative effect Effects 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 230000006780 non-homologous end joining Effects 0.000 description 1
- 239000003956 nonsteroidal anti androgen Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000020520 nucleotide-excision repair Effects 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 229960004390 palbociclib Drugs 0.000 description 1
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 1
- 238000004091 panning Methods 0.000 description 1
- FPOHNWQLNRZRFC-ZHACJKMWSA-N panobinostat Chemical compound CC=1NC2=CC=CC=C2C=1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FPOHNWQLNRZRFC-ZHACJKMWSA-N 0.000 description 1
- 210000002990 parathyroid gland Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 238000012831 peritoneal equilibrium test Methods 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229950010773 pidilizumab Drugs 0.000 description 1
- 208000021310 pituitary gland adenoma Diseases 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 108040000983 polyphosphate:AMP phosphotransferase activity proteins Proteins 0.000 description 1
- 238000012636 positron electron tomography Methods 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 238000012877 positron emission topography Methods 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 208000016800 primary central nervous system lymphoma Diseases 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 108010079891 prostein Proteins 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000018883 protein targeting Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- BWESROVQGZSBRX-UHFFFAOYSA-N pyrido[3,2-d]pyrimidine Chemical compound C1=NC=NC2=CC=CN=C21 BWESROVQGZSBRX-UHFFFAOYSA-N 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 201000007444 renal pelvis carcinoma Diseases 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052895 riebeckite Inorganic materials 0.000 description 1
- 229960003452 romidepsin Drugs 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 description 1
- 108010091666 romidepsin Proteins 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229940121328 seclidemstat Drugs 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 230000003007 single stranded DNA break Effects 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000037439 somatic mutation Effects 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000002720 stereotactic body radiation therapy Methods 0.000 description 1
- 238000002719 stereotactic radiosurgery Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 101150047061 tag-72 gene Proteins 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960001712 testosterone propionate Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 229950004742 tigatuzumab Drugs 0.000 description 1
- 230000037426 transcriptional repression Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- 229940049679 trastuzumab deruxtecan Drugs 0.000 description 1
- 229960001612 trastuzumab emtansine Drugs 0.000 description 1
- 229950007217 tremelimumab Drugs 0.000 description 1
- 229950001415 tucidinostat Drugs 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 229950000302 vadastuximab Drugs 0.000 description 1
- 229940121516 vafidemstat Drugs 0.000 description 1
- 229960001183 venetoclax Drugs 0.000 description 1
- LQBVNQSMGBZMKD-UHFFFAOYSA-N venetoclax Chemical compound C=1C=C(Cl)C=CC=1C=1CC(C)(C)CCC=1CN(CC1)CCN1C(C=C1OC=2C=C3C=CNC3=NC=2)=CC=C1C(=O)NS(=O)(=O)C(C=C1[N+]([O-])=O)=CC=C1NCC1CCOCC1 LQBVNQSMGBZMKD-UHFFFAOYSA-N 0.000 description 1
- 229940065658 vidaza Drugs 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960000922 vinflunine Drugs 0.000 description 1
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
- 208000013013 vulvar carcinoma Diseases 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
- A61K51/1021—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against cytokines, e.g. growth factors, VEGF, TNF, lymphokines or interferons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
- A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
- A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
- A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
- A61K51/1096—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies radioimmunotoxins, i.e. conjugates being structurally as defined in A61K51/1093, and including a radioactive nucleus for use in radiotherapeutic applications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
- A61K2039/507—Comprising a combination of two or more separate antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Chemistry (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Optics & Photonics (AREA)
- Oncology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
Abstract
Provided are compositions and methods for treating a solid cancer such as a HER3-positive tumor in a subject by administering an effective amount of a HER3-targeting agent labeled with a radionuclide such as 225Ac, 177Lu, 131I, 90Y, 213Bi, 211At, 213Bi, 227Th, or 212Pb, alone or in combination with other therapeutic agents or modalities. The effective amount of the radiolabeled HER3-targeting agent may be a maximum tolerate dose administered in a single bolus or in fractionated doses that together equal the maximum tolerated dose.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[00011 This application claims priority to each of International Application No. PCT/US21/56259 filed October 22, 2021, and its priority applications U.S. provisional application serial nos. 63,250,725 filed September 30, 2021 and 63/226,699 filed July 28, 2021;
to U.S. provisional patent application no. 63/118,181 filed November 25, 2020;
and to U.S. provisional patent application no. 63/116,225 filed November 20, 2020, each of the foregoing applications hereby incorporated by reference in its entirety.
SEQUENCE LISTING
[00011 This application claims priority to each of International Application No. PCT/US21/56259 filed October 22, 2021, and its priority applications U.S. provisional application serial nos. 63,250,725 filed September 30, 2021 and 63/226,699 filed July 28, 2021;
to U.S. provisional patent application no. 63/118,181 filed November 25, 2020;
and to U.S. provisional patent application no. 63/116,225 filed November 20, 2020, each of the foregoing applications hereby incorporated by reference in its entirety.
SEQUENCE LISTING
[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on November 22, 2021, is named ATNM-010PCT SL_ST25.txt and is 191,107 bytes in size.
FIELD OF THE INVENTION
[0001] The present invention relates to the field of radiotherapeutics.
BACKGROUND OF THE INVENTION
[0002] ErbB3/HER3 is a type I transmembrane glycoprotein that is a member of the erythroblastic oncogene B (ErbB) family of tyrosine kinase receptors (EGER, BER2, HER3, and HER4). Signaling through HER3 can be activated in a ligand-dependent or ligand-independent manner. In the absence of ligand, HER3 receptor molecules are normally expressed at the cell surface as monomers with a conformation that prevents receptor dimerization.
In this conformation, the dimerization loop of subdomain II makes intramolecular contact with a pocket on subdomain IV. Binding of a HER3 ligand such as a neuregulin (NRG), e.g.
NRG1 (also known as heregulin, HRG) or NRG2, to subdomains I and III of the extracellular region causes a conformational change that results in exposure of the dimerization loop of subdomain II, facilitating receptor dimerization and signaling. Certain cancer-associated mutations in HER3 disrupt this interaction between subdomains II and IV, i.e., the interaction required for formation of the inactive 'closed' conformation, and thereby cause constitutive presentation of the dimerization loop and activation of HER3-mediated signaling in the absence of ligand binding.
FIELD OF THE INVENTION
[0001] The present invention relates to the field of radiotherapeutics.
BACKGROUND OF THE INVENTION
[0002] ErbB3/HER3 is a type I transmembrane glycoprotein that is a member of the erythroblastic oncogene B (ErbB) family of tyrosine kinase receptors (EGER, BER2, HER3, and HER4). Signaling through HER3 can be activated in a ligand-dependent or ligand-independent manner. In the absence of ligand, HER3 receptor molecules are normally expressed at the cell surface as monomers with a conformation that prevents receptor dimerization.
In this conformation, the dimerization loop of subdomain II makes intramolecular contact with a pocket on subdomain IV. Binding of a HER3 ligand such as a neuregulin (NRG), e.g.
NRG1 (also known as heregulin, HRG) or NRG2, to subdomains I and III of the extracellular region causes a conformational change that results in exposure of the dimerization loop of subdomain II, facilitating receptor dimerization and signaling. Certain cancer-associated mutations in HER3 disrupt this interaction between subdomains II and IV, i.e., the interaction required for formation of the inactive 'closed' conformation, and thereby cause constitutive presentation of the dimerization loop and activation of HER3-mediated signaling in the absence of ligand binding.
[0003] Antibodies that target HER3 may be employed to target specific cancer cells, particularly certain solid cancers. HER3 is overexpressed in several types of cancers such as breast, gastrointestinal, and pancreatic cancers. A correlation between the expression of IIER2/HER3 and the progression from a non-invasive stage to an invasive stage of these cancers has been shown. Agents that interfere with HER3-mediated signaling, such as anti-HER3 antibodies, may enable the establishment of a robust immune response to the cancer cells that would be otherwise inadequate using conventional therapy.
[0004] Accordingly, one object of the presently disclosed invention is to provide therapeutically effective radiolabeled 1-IER3 targeting agents, such as for the treatment of HER3-positive cancers. A related object of the presently disclosed invention is to provide therapeutic methods including administration of such a radiolabeled HER3 targeting agent, either alone or in combination with one or more additional therapeutic agents.
SUMMARY OF THE INVENTION
SUMMARY OF THE INVENTION
[0005] The present invention provides a HER3 targeting agent, such as a monoclonal antibody, peptide, or small molecule that targets HER3, labeled with a radioisotope, and methods of diagnosing and/or treating HER3-positive (HER3-expressing) cancers using the radiolabeled HER3 targeting agent.
[0006] According to certain aspects of the present invention, the radiolabeled targeting agent useful for diagnostics purposes may be an anti-HER3 antibody, peptide, or small molecule including a radioisotope, such as 68Ga, 64¨u, "Zr, or 177Lu.
[0007] According to certain other aspects, the radiolabeled 1-IER3 targeting agent useful for therapeutic interventions may be an anti -HER3 antibody, peptide, or small molecule 1311, 1251, 1231, 90y, 177Lu, 186Re, 153sm, 32p, 225Ac, including a radioisotope, such as: t=c_ 89Sr, 213Bi, 213po, 211At, 212Bi, 213Bi, 223Ra, 227Th, 149Tb, 137cs, 212Pb, or combinations thereof.
According to certain preferred aspects, the radiolabeled HER3 targeting agent may include 1311, 90y, 177Lh, 225Ac, 213Bi, 211At, 227Th, or 212ph.
[0006] According to certain aspects, the HER3-positive cancer may be a solid tumor.
[0009] Therapeutic methods of the presently disclosed invention generally include administering to a patient a therapeutically effective amount of the radiolabeled HER3 targeting agent According to certain aspects, the effective amount of the radiolabeled HER3 targeting agent may be a maximum tolerated dose (MTD) or may be a fractioned dose wherein the total amount of radiation administered in the fractioned doses is the MTD.
[0010] According to certain aspects, provided and/or used is a composition or quantity of the HER3 targeting agent that includes a radiolabeled fraction and a non-radiolabeled fraction of the HER3 targeting agent. As such, an effective amount of the HER3 targeting agent may include a total protein dose of less than 100 mg, such as from 5 mg to 60 mg, or 5 mg to 45 mg.
According to certain aspects, the total protein dose may be from 0.001 mg/kg to 3 mg/kg body weight of the subject, such as from 0.005 mg/kg to 2 mg/kg body weight of the subject.
According to certain aspects, the total protein dose may be less than 2mg/kg, or less than 1 mg/kg, less than 0.5 mg/kg, or even less than 0.1mg/kg. A portion of the total protein dose is radiolabeled (i . e., radio-conjugate) as indicated, wherein the effective amount of the radiolabeled HER3 targeting agent may depend on the specific radioisotope selected.
Preferred radioisotopes for therapeutic interventions include 225 = c, 177Lu, 131I, 90y, 213Bi, 2" At, 227Th, or 212Pb. Thus, the FIER3 targeting agent may include a radiolabeled fraction and an unlabeled fraction.
[0011] According to certain aspects, an effective amount of a 1-IER3 targeting agent in terms of radiation dose, i.e., of the radiolabeled portion thereof, such as an 225Ac-anti-HER3 antibody, peptide, or small molecule, may include a dose of 0.1 to 20 Ci/kg body weight of the subject, such as 0.1 to 10 Ci/kg or 0.1 to 5 uCi/kg body weight of the subject, or 0.5 to 20 Ci/kg or 1 to 10 uCi/kg body weight of the subject.
[0012] According to certain aspects, the effective amount of the HER3 targeting agent, i.e., the radiolabeled portion thereof, such as an 225Ac-anti-HER3 antibody, peptide, or small molecule may depend on the configuration of the targeting agent, i.e., full length antibody or antigen-binding antibody fragment (e.g., Fab, Fab2, minibody, nanobody, etc) such as any of those disclosed herein. For example, when the HER3 targeting agent includes an 225Ac-anti-HER3 antibody that is a full-length antibody, the dose may be below 5 uCi/kg body weight of the subject, such as 0.1 to 5 uCi/kg body weight of the subject. Alternatively, when the HER3 targeting agent includes an 225Ac-anti-HER3 antibody that is a fragment, the dose may be greater than 5 uCi/kg body weight of the subject, such as 5 to 20 uCi/kg body weight of the subject.
[0013] According to certain aspects, the HE R3 targeting agent is an anti-HER3 antibody, such as a monoclonal antibody or an antigen binding fragment thereof, such as an IgG or an antigen binding fragment thereof, such as one that binds to an epitope of HER3 recognized by Patritumab from Daiichi Sankyo, Seribantumab (MM-121) from Merrimack Pharmaceuticals, Lumretuzumab from Roche, Elgemtumab from Novartis, GSK2849330 from GlaxoSmithKline, CDX-3379 of Celldex Therapeutics, EV20 and MP-RM-1 from MediPharma, ISU104 from Isu Abxis Co., HMBD-001 (10D1F) from Hummingbird Bioscience Pte., REGN1400 from Regeneron Pharmaceuticals, and/or AV-203 from AVE0 Oncology. According to certain aspects, the anti-HER3 antibody is selected from one or more of Patritumab, Seribantumab, Lumretuzumab, Elgemtumab, AV-203, CDX-3379, or GSK2849330.
[0014] According to certain aspects, the HER3 targeting agent may be administered according to a dosing schedule selected from the group consisting of one dose every 7, 10, 12, 14, 20, 24, 28, 35, and 42 days throughout a treatment period, wherein the treatment period includes at least two doses.
[0015] According to certain aspects, the HER3 targeting agent may be administered according to a dose schedule that includes 2 doses, such as on days 1 and 5, 6, 7, 8, 9, or 10 of a treatment period, or days 1 and 8 of a treatment period.
[0016] According to certain aspects, the 1-IER3 targeting agent may be administered as a single bolus or infusion in a single subject specific dose [0017] According to certain aspects, the methods may further include administration of one or more further therapeutic agents, such as a chemotherapeutic agent, a small molecule drug, an anti-inflammatory agent, an immunosuppressive agent, an immunomodulatory agent, an antimyeloma agent, a cytokine, or a combination thereof. Exemplary chemotherapeutic agents include at least radiosensitizers that may synergize with the radiolabeled HER3 targeting agent, such as temozolomide, cisplatin, and/or fluorouracil [0018] According to certain aspects, the methods may further include administration of one or more immune checkpoint therapies. Exemplary immune checkpoint therapies include an antibody against CTLA-4, PD-1, TIM-3, VISTA, BTLA, LAG-3, TIGIT, CD28, 0X40, GITR, CD137, CD40, CD4OL, CD27, HVEM, PD-L1, PD-L2, PD-L3, PD-L4, CD80, CD86, CD137-L, GITR-L, CD226, B7-H3, B7-H4, BTLA, TIGIT, GALS, KIR, 2B4, CD160, CGEN-15049, or any combination thereof. According to certain aspects, the immune checkpoint therapy may include an antibody against an immune checkpoint protein selected from the group consisting of an antibody against PD-I, PD-LI, PD-L2, CTLA-4, CD137, and a combination thereof.
[0019] According to certain aspects, the immune checkpoint therapy may be administered to a subject in an effective amount, such as a dose of 0.1 mg/kg to 50 mg/kg of the patient's body weight, such as 0.1-5 mg/kg, or 5-30 mg/kg.
[0020] According to certain aspects, the methods may further include administration of one or more DNA damage response inhibitors (DDRi). Exemplary DDRi agents one or more antibodies or small molecules targeting poly(ADP-ribose) polymerase (i.e., a poly(ADP-ribose) polymerase inhibitor or PARPi). The PARPi may, for example, include olaparib, niraparib, rucaparib, talazoparib, or any combination thereof. According to certain aspects, the PARPi may be provided in a subject effective amount including 0.1 mg/day ¨ 1200 mg/day, such as 0.100 mg/day ¨ 600 mg/day, or 0,25 mg/day ¨ 1 mg/day. Exemplary subject effective amounts include 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg, and 1000 mg, taken orally in one or two doses per day.
[0021] Another exemplary DDRi includes an inhibitor of Ataxia telangiectasia mutated (ATM), Ataxia talangiectasia mutated and Rad-3 related (ATR), or Weel.
Exemplary inhibitors of ATM include KU-55933, KU-59403, wortmannin, CP466722, and KU-60019.
Exemplary inhibitors of ATR include at least Schisandrin B, NU6027, NVP-BEA235, VE-821, VE-822, AZ20, and AZD6738 Exemplary inhibitors of Weel include AZD-1775 (i.e., adavosertib).
[0022] According to certain aspects, the methods may further include administration of one or more CD47 blockades. The CD47 blockade may include a monoclonal antibody, SIRPa-Fc fusion protein or other molecule that prevents CD47 binding to SIRPa or otherwise blocks or downregulates the immunosuppressive activity of CD47, such as magrolimab, lemzoparlimab, A0-176, AK117, IMC-002, IBI-188, 1.131-322, BI 766063, ZL-1201, AXL148, RRx-001, ES004, SRF231, SHR-1603, TJC4, TTI-621, or TTI-622 Exemplary effective doses for the blockade include 0.05 to 5 mg/kg patient weight. The CD47 blockade may also include agents that modulate the expression of CD47 and/or SIRPa, such as a nucleic acid approach, e.g., anti-sense, RNAi, or pRNA approaches. Exemplary CD47 blockades also include phosphorodiamidate morpholino oligomers (PMO) that block translation of CD47 such as MET-001.
[0023] According to certain aspects, the methods may further include administration of a combination of further therapeutic agents. Exemplary combinations include at least one or more DDRi and/or one or more immune checkpoint therapies and/or one or more CD47 blockades and/or one or more chemotherapeutics and/or one or more small molecule anti-cancer drugs and/or one or more targeting agents directed against different cancer-associated antigens.
[0024] According to certain aspects, the radiolabeled HER3 targeting agent and the one or more further therapeutic agents may be administered simultaneously or sequentially. When more than one additional therapeutic agent is administered, the agents may be administered simultaneously or sequentially.
[0025] According to certain aspects of the present invention, the radiolabeled targeting agent may be a multi-specific targeting agent such as a multi-specific antibody or bispecific antibody, in which at least one part recognizes HER3. Thus, the methods may include administering to the subject an effective amount of a multi-specific antibody, wherein the multi-specific antibody includes: a first target recognition component which specifically binds to an epitope of HER3, and a second target recognition component which specifically binds to a different epitope of HER3 than the first target recognition component, or to an epitope of a different antigen such as a different cancer-associated antigen According to certain aspects, the HER3 targeting agent is a multi-specific antibody against a first epitope of HER3 and at least a second epitope of HER3, or against 1-IER3 and at least a second (different) antigen. Exemplary multi-specific antibodies that may be radiolabeled for diagnostic and/or therapeutic use according to the invention include bispecific antibodies against HER3/HER2 such as MM-111 from Merrimack Pharmaceuticals or MCLA-128 from Merus N.V.; or against IGF-such as MM-141 (i.e., Istiratumab) from Merrimack Pharmaceuticals; or against such as MEHD7945A (i.e., Duligotumab) from Roche or any of the cetuximab-based bispecific or multi-specific zybodies from Zyngenia Inc.
[0026] According to certain aspects, a composition is provided that includes a mixture of a HER3 targeting agent such as an antibody against HER3 and one or more further targeting agents, such as antibodies, targeting/against one or more different cancer associated antigens, wherein one or more of the HER3 targeting agent and the other targeting agent(s) may be radiolabeled or non-radiolabeled in any combination. An exemplary antibody composition including an antibody mixture includes at least Sym013 from Symphogen having six monoclonal antibodies against EGFR (HERD, HER2, and HER3. In one aspect, one or more of the antibodies of the Sym013 may be radiolabeled in any combination, such as at least a HER3 antibody and none or one or more of the antibodies against EGFR and HER2.
[0027] Additional features, advantages, and aspects of the invention may be set forth or apparent from consideration of the following detailed description, drawings if any, and claims.
Moreover, it is to be understood that both the foregoing summary of the invention and the following detailed description are exemplary and intended to provide further explanation without limiting the scope of the invention as claimed.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] FIG. 1 provides the amino acid sequences of the N-terminal region, complementarity determining regions, and variable regions of the heavy and light chains of a HER3 monoclonal antibody that may be embodied in various aspects of the present invention.
[0029] FIG. 2 provides the amino acid sequences of the full-length heavy and light chains, with and without leader sequences, of a ITER3 monoclonal antibody that may be embodied in various aspects of the present invention.
[0030] FIG 3 shows ELISA assay binding characteristics of an Ac225 labeled DOTA-conjugated anti-HER3 monoclonal antibody versus the unmodified anti-HER3 antibody and a non-specific antibody (IgG), demonstrating that the modifications do not materially affect immune reactivity to HER3.
[0031] FIG 4 is a graph showing the results of flow cytometry assays examining the binding of the 225Ac-HER3-ARC, the unmodified anti-HER3 mAb, non-specific antibody control (IgG), and secondary antibody only control to HER3-positive NCI-H1975 cells (human lung adenocarcinorna, NSCLC) and BxPC-3 cells (human pancreatic adenocarcinoma) [0032] FIG. 5 is a graph showing the in vitro cytotoxic effect of 225Ac-HER3-ARC to HER3-positive cell line NCI-H1975 as a function of radiation dose.
[0033] FIG. 6A is a graph showing that 225Ac-1-IER3-ARC upregulates cell surface calreticulin (CRT) in NCI-H1975 cells [0034] FIG. 61B is a graph showing that 225Ac-IIER3-ARC upregulates CD47 on NCI-H1975 cells.
[0035] FIG. 7A is a graph showing results of a phagocytosis assay demonstrating that the combination of 225Ac-HER3-ARC and an anti-CD47 blocking antibody enhanced phagocytosis of BxPC-3 cells versus either treatment alone
According to certain preferred aspects, the radiolabeled HER3 targeting agent may include 1311, 90y, 177Lh, 225Ac, 213Bi, 211At, 227Th, or 212ph.
[0006] According to certain aspects, the HER3-positive cancer may be a solid tumor.
[0009] Therapeutic methods of the presently disclosed invention generally include administering to a patient a therapeutically effective amount of the radiolabeled HER3 targeting agent According to certain aspects, the effective amount of the radiolabeled HER3 targeting agent may be a maximum tolerated dose (MTD) or may be a fractioned dose wherein the total amount of radiation administered in the fractioned doses is the MTD.
[0010] According to certain aspects, provided and/or used is a composition or quantity of the HER3 targeting agent that includes a radiolabeled fraction and a non-radiolabeled fraction of the HER3 targeting agent. As such, an effective amount of the HER3 targeting agent may include a total protein dose of less than 100 mg, such as from 5 mg to 60 mg, or 5 mg to 45 mg.
According to certain aspects, the total protein dose may be from 0.001 mg/kg to 3 mg/kg body weight of the subject, such as from 0.005 mg/kg to 2 mg/kg body weight of the subject.
According to certain aspects, the total protein dose may be less than 2mg/kg, or less than 1 mg/kg, less than 0.5 mg/kg, or even less than 0.1mg/kg. A portion of the total protein dose is radiolabeled (i . e., radio-conjugate) as indicated, wherein the effective amount of the radiolabeled HER3 targeting agent may depend on the specific radioisotope selected.
Preferred radioisotopes for therapeutic interventions include 225 = c, 177Lu, 131I, 90y, 213Bi, 2" At, 227Th, or 212Pb. Thus, the FIER3 targeting agent may include a radiolabeled fraction and an unlabeled fraction.
[0011] According to certain aspects, an effective amount of a 1-IER3 targeting agent in terms of radiation dose, i.e., of the radiolabeled portion thereof, such as an 225Ac-anti-HER3 antibody, peptide, or small molecule, may include a dose of 0.1 to 20 Ci/kg body weight of the subject, such as 0.1 to 10 Ci/kg or 0.1 to 5 uCi/kg body weight of the subject, or 0.5 to 20 Ci/kg or 1 to 10 uCi/kg body weight of the subject.
[0012] According to certain aspects, the effective amount of the HER3 targeting agent, i.e., the radiolabeled portion thereof, such as an 225Ac-anti-HER3 antibody, peptide, or small molecule may depend on the configuration of the targeting agent, i.e., full length antibody or antigen-binding antibody fragment (e.g., Fab, Fab2, minibody, nanobody, etc) such as any of those disclosed herein. For example, when the HER3 targeting agent includes an 225Ac-anti-HER3 antibody that is a full-length antibody, the dose may be below 5 uCi/kg body weight of the subject, such as 0.1 to 5 uCi/kg body weight of the subject. Alternatively, when the HER3 targeting agent includes an 225Ac-anti-HER3 antibody that is a fragment, the dose may be greater than 5 uCi/kg body weight of the subject, such as 5 to 20 uCi/kg body weight of the subject.
[0013] According to certain aspects, the HE R3 targeting agent is an anti-HER3 antibody, such as a monoclonal antibody or an antigen binding fragment thereof, such as an IgG or an antigen binding fragment thereof, such as one that binds to an epitope of HER3 recognized by Patritumab from Daiichi Sankyo, Seribantumab (MM-121) from Merrimack Pharmaceuticals, Lumretuzumab from Roche, Elgemtumab from Novartis, GSK2849330 from GlaxoSmithKline, CDX-3379 of Celldex Therapeutics, EV20 and MP-RM-1 from MediPharma, ISU104 from Isu Abxis Co., HMBD-001 (10D1F) from Hummingbird Bioscience Pte., REGN1400 from Regeneron Pharmaceuticals, and/or AV-203 from AVE0 Oncology. According to certain aspects, the anti-HER3 antibody is selected from one or more of Patritumab, Seribantumab, Lumretuzumab, Elgemtumab, AV-203, CDX-3379, or GSK2849330.
[0014] According to certain aspects, the HER3 targeting agent may be administered according to a dosing schedule selected from the group consisting of one dose every 7, 10, 12, 14, 20, 24, 28, 35, and 42 days throughout a treatment period, wherein the treatment period includes at least two doses.
[0015] According to certain aspects, the HER3 targeting agent may be administered according to a dose schedule that includes 2 doses, such as on days 1 and 5, 6, 7, 8, 9, or 10 of a treatment period, or days 1 and 8 of a treatment period.
[0016] According to certain aspects, the 1-IER3 targeting agent may be administered as a single bolus or infusion in a single subject specific dose [0017] According to certain aspects, the methods may further include administration of one or more further therapeutic agents, such as a chemotherapeutic agent, a small molecule drug, an anti-inflammatory agent, an immunosuppressive agent, an immunomodulatory agent, an antimyeloma agent, a cytokine, or a combination thereof. Exemplary chemotherapeutic agents include at least radiosensitizers that may synergize with the radiolabeled HER3 targeting agent, such as temozolomide, cisplatin, and/or fluorouracil [0018] According to certain aspects, the methods may further include administration of one or more immune checkpoint therapies. Exemplary immune checkpoint therapies include an antibody against CTLA-4, PD-1, TIM-3, VISTA, BTLA, LAG-3, TIGIT, CD28, 0X40, GITR, CD137, CD40, CD4OL, CD27, HVEM, PD-L1, PD-L2, PD-L3, PD-L4, CD80, CD86, CD137-L, GITR-L, CD226, B7-H3, B7-H4, BTLA, TIGIT, GALS, KIR, 2B4, CD160, CGEN-15049, or any combination thereof. According to certain aspects, the immune checkpoint therapy may include an antibody against an immune checkpoint protein selected from the group consisting of an antibody against PD-I, PD-LI, PD-L2, CTLA-4, CD137, and a combination thereof.
[0019] According to certain aspects, the immune checkpoint therapy may be administered to a subject in an effective amount, such as a dose of 0.1 mg/kg to 50 mg/kg of the patient's body weight, such as 0.1-5 mg/kg, or 5-30 mg/kg.
[0020] According to certain aspects, the methods may further include administration of one or more DNA damage response inhibitors (DDRi). Exemplary DDRi agents one or more antibodies or small molecules targeting poly(ADP-ribose) polymerase (i.e., a poly(ADP-ribose) polymerase inhibitor or PARPi). The PARPi may, for example, include olaparib, niraparib, rucaparib, talazoparib, or any combination thereof. According to certain aspects, the PARPi may be provided in a subject effective amount including 0.1 mg/day ¨ 1200 mg/day, such as 0.100 mg/day ¨ 600 mg/day, or 0,25 mg/day ¨ 1 mg/day. Exemplary subject effective amounts include 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg, and 1000 mg, taken orally in one or two doses per day.
[0021] Another exemplary DDRi includes an inhibitor of Ataxia telangiectasia mutated (ATM), Ataxia talangiectasia mutated and Rad-3 related (ATR), or Weel.
Exemplary inhibitors of ATM include KU-55933, KU-59403, wortmannin, CP466722, and KU-60019.
Exemplary inhibitors of ATR include at least Schisandrin B, NU6027, NVP-BEA235, VE-821, VE-822, AZ20, and AZD6738 Exemplary inhibitors of Weel include AZD-1775 (i.e., adavosertib).
[0022] According to certain aspects, the methods may further include administration of one or more CD47 blockades. The CD47 blockade may include a monoclonal antibody, SIRPa-Fc fusion protein or other molecule that prevents CD47 binding to SIRPa or otherwise blocks or downregulates the immunosuppressive activity of CD47, such as magrolimab, lemzoparlimab, A0-176, AK117, IMC-002, IBI-188, 1.131-322, BI 766063, ZL-1201, AXL148, RRx-001, ES004, SRF231, SHR-1603, TJC4, TTI-621, or TTI-622 Exemplary effective doses for the blockade include 0.05 to 5 mg/kg patient weight. The CD47 blockade may also include agents that modulate the expression of CD47 and/or SIRPa, such as a nucleic acid approach, e.g., anti-sense, RNAi, or pRNA approaches. Exemplary CD47 blockades also include phosphorodiamidate morpholino oligomers (PMO) that block translation of CD47 such as MET-001.
[0023] According to certain aspects, the methods may further include administration of a combination of further therapeutic agents. Exemplary combinations include at least one or more DDRi and/or one or more immune checkpoint therapies and/or one or more CD47 blockades and/or one or more chemotherapeutics and/or one or more small molecule anti-cancer drugs and/or one or more targeting agents directed against different cancer-associated antigens.
[0024] According to certain aspects, the radiolabeled HER3 targeting agent and the one or more further therapeutic agents may be administered simultaneously or sequentially. When more than one additional therapeutic agent is administered, the agents may be administered simultaneously or sequentially.
[0025] According to certain aspects of the present invention, the radiolabeled targeting agent may be a multi-specific targeting agent such as a multi-specific antibody or bispecific antibody, in which at least one part recognizes HER3. Thus, the methods may include administering to the subject an effective amount of a multi-specific antibody, wherein the multi-specific antibody includes: a first target recognition component which specifically binds to an epitope of HER3, and a second target recognition component which specifically binds to a different epitope of HER3 than the first target recognition component, or to an epitope of a different antigen such as a different cancer-associated antigen According to certain aspects, the HER3 targeting agent is a multi-specific antibody against a first epitope of HER3 and at least a second epitope of HER3, or against 1-IER3 and at least a second (different) antigen. Exemplary multi-specific antibodies that may be radiolabeled for diagnostic and/or therapeutic use according to the invention include bispecific antibodies against HER3/HER2 such as MM-111 from Merrimack Pharmaceuticals or MCLA-128 from Merus N.V.; or against IGF-such as MM-141 (i.e., Istiratumab) from Merrimack Pharmaceuticals; or against such as MEHD7945A (i.e., Duligotumab) from Roche or any of the cetuximab-based bispecific or multi-specific zybodies from Zyngenia Inc.
[0026] According to certain aspects, a composition is provided that includes a mixture of a HER3 targeting agent such as an antibody against HER3 and one or more further targeting agents, such as antibodies, targeting/against one or more different cancer associated antigens, wherein one or more of the HER3 targeting agent and the other targeting agent(s) may be radiolabeled or non-radiolabeled in any combination. An exemplary antibody composition including an antibody mixture includes at least Sym013 from Symphogen having six monoclonal antibodies against EGFR (HERD, HER2, and HER3. In one aspect, one or more of the antibodies of the Sym013 may be radiolabeled in any combination, such as at least a HER3 antibody and none or one or more of the antibodies against EGFR and HER2.
[0027] Additional features, advantages, and aspects of the invention may be set forth or apparent from consideration of the following detailed description, drawings if any, and claims.
Moreover, it is to be understood that both the foregoing summary of the invention and the following detailed description are exemplary and intended to provide further explanation without limiting the scope of the invention as claimed.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] FIG. 1 provides the amino acid sequences of the N-terminal region, complementarity determining regions, and variable regions of the heavy and light chains of a HER3 monoclonal antibody that may be embodied in various aspects of the present invention.
[0029] FIG. 2 provides the amino acid sequences of the full-length heavy and light chains, with and without leader sequences, of a ITER3 monoclonal antibody that may be embodied in various aspects of the present invention.
[0030] FIG 3 shows ELISA assay binding characteristics of an Ac225 labeled DOTA-conjugated anti-HER3 monoclonal antibody versus the unmodified anti-HER3 antibody and a non-specific antibody (IgG), demonstrating that the modifications do not materially affect immune reactivity to HER3.
[0031] FIG 4 is a graph showing the results of flow cytometry assays examining the binding of the 225Ac-HER3-ARC, the unmodified anti-HER3 mAb, non-specific antibody control (IgG), and secondary antibody only control to HER3-positive NCI-H1975 cells (human lung adenocarcinorna, NSCLC) and BxPC-3 cells (human pancreatic adenocarcinoma) [0032] FIG. 5 is a graph showing the in vitro cytotoxic effect of 225Ac-HER3-ARC to HER3-positive cell line NCI-H1975 as a function of radiation dose.
[0033] FIG. 6A is a graph showing that 225Ac-1-IER3-ARC upregulates cell surface calreticulin (CRT) in NCI-H1975 cells [0034] FIG. 61B is a graph showing that 225Ac-IIER3-ARC upregulates CD47 on NCI-H1975 cells.
[0035] FIG. 7A is a graph showing results of a phagocytosis assay demonstrating that the combination of 225Ac-HER3-ARC and an anti-CD47 blocking antibody enhanced phagocytosis of BxPC-3 cells versus either treatment alone
8 [0036] FIG. 713 is a graph showing results of a phagocytosis assay demonstrating that the combination of 225Ac-HER3-ARC and an anti-CD47 blocking antibody enhanced phagocytosis of NCI-H1975 cells versus either treatment alone.
[0037] FIG. 8 is graph showing the effects on tumor growth, in a human tumor (NCI-H1975 cell) mouse xenograft model, of a 225Ac-HER3-ARC at different radiation doses and in combination with an anti-CD47 blocking antibody.
[0038] FIG. 9 is a graph showing body weight over time for the subjects of the experiment described in FIG. 8.
[0039] FIG. 10 is a graph showing the probability of survival over time for the experimental group subjects of the experiment described in FIG. 8 [0040] FIG. 11 is a graph showing the comparative effects on tumor growth of vehicle (control), CD47 blocking antibody magrolimab alone, 225Actrastuzumab alone, and the combination of magrolimab and 225Ac-trastuzumab in an NGS mouse xenograft model using the HE,R2-positive SK-0V3 human ovarian cancer cell line.
[0041] FIG. 12 is a graph showing the comparative effects on tumor growth of vehicle (control), magrolimab alone, 177Lu-trastuzumab alone, and the combination of magrolimab and 177Lu-trastuzumab in an NGS mouse xenograft model using the SK-0V3 human ovarian cancer cell line.
DETAILED DESCRIPTION OF THE INVENTION
[0042] In one aspect, the presently disclosed invention provides compositions and methods for the treatment of cancers expressing FIER3, i.e., HER3-positive cancers. This aspect generally includes administering to a mammalian subject in need of treatment, such as a human patient, an effective amount of a radiolabeled HER3 targeting agent, such as a radiolabeled antibody, peptide, or small molecule targeted to HER3, alone or in combination with one or more additional therapeutic agents and/or therapeutic modalities/treatments.
[0043] Additional therapeutic agents and modalities that may be used include, for example, at least one or more immune checkpoint therapy and/or one or more inhibitors of a component of the DNA damage response pathway (i.e., a DNA damage response inhibitor, DDRi, such as one or more agents against poly(ADP-ribose) polymerase, i.e., PARPi) and/or one or more CD47/SIRPa axis blockades and/or one or more chemotherapeutic agents such as
[0037] FIG. 8 is graph showing the effects on tumor growth, in a human tumor (NCI-H1975 cell) mouse xenograft model, of a 225Ac-HER3-ARC at different radiation doses and in combination with an anti-CD47 blocking antibody.
[0038] FIG. 9 is a graph showing body weight over time for the subjects of the experiment described in FIG. 8.
[0039] FIG. 10 is a graph showing the probability of survival over time for the experimental group subjects of the experiment described in FIG. 8 [0040] FIG. 11 is a graph showing the comparative effects on tumor growth of vehicle (control), CD47 blocking antibody magrolimab alone, 225Actrastuzumab alone, and the combination of magrolimab and 225Ac-trastuzumab in an NGS mouse xenograft model using the HE,R2-positive SK-0V3 human ovarian cancer cell line.
[0041] FIG. 12 is a graph showing the comparative effects on tumor growth of vehicle (control), magrolimab alone, 177Lu-trastuzumab alone, and the combination of magrolimab and 177Lu-trastuzumab in an NGS mouse xenograft model using the SK-0V3 human ovarian cancer cell line.
DETAILED DESCRIPTION OF THE INVENTION
[0042] In one aspect, the presently disclosed invention provides compositions and methods for the treatment of cancers expressing FIER3, i.e., HER3-positive cancers. This aspect generally includes administering to a mammalian subject in need of treatment, such as a human patient, an effective amount of a radiolabeled HER3 targeting agent, such as a radiolabeled antibody, peptide, or small molecule targeted to HER3, alone or in combination with one or more additional therapeutic agents and/or therapeutic modalities/treatments.
[0043] Additional therapeutic agents and modalities that may be used include, for example, at least one or more immune checkpoint therapy and/or one or more inhibitors of a component of the DNA damage response pathway (i.e., a DNA damage response inhibitor, DDRi, such as one or more agents against poly(ADP-ribose) polymerase, i.e., PARPi) and/or one or more CD47/SIRPa axis blockades and/or one or more chemotherapeutic agents such as
9 radiosensitizers, and/or one or more small molecule oncology drugs such as tyrosine kinase inhibitors, and/or one or more targeting agents against different antigens..
[0044] The presently disclosed invention further provides methods for identifying, imaging and/or diagnosing ITER3-positive cancers in a subject. The presently disclosed invention further provides methods for identifying, imaging and/or diagnosing HER3-positive cancer in a subject, followed by treating those subjects according to any of the methods disclosed herein.
[0045] Definitions and Abbreviations [0046] The singular forms "a," "an," "the" and the like include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an"
antibody includes both a single antibody and a plurality of different antibodies.
100471 The words "comprising" and forms of the word -comprising" as well as the word "including" and forms of the word "including," as used in this description and in the claims, do not limit the inclusion of elements beyond what is referred to. Additionally, although throughout the present disclosure various aspects or elements thereof are described in terms of "including"
or "comprising,- corresponding aspects or elements thereof described in terms of "consisting essentially of' or -consisting of' are similarly disclosed. For example, while certain aspects of the invention have been described in terms of a method "including" or "comprising"
administering a radiolabeled targeting agent, corresponding methods instead reciting "consisting essentially of' or "consisting of' administering the radiolabeled target are also within the scope of said aspects and disclosed by this disclosure.
[0048] The term -about" when used in this disclosure in connection with a numerical designation or value, e.g., in describing temperature, time, amount, and concentration, including in the description of a range, indicates a variance of +10% and, within that larger variance, variances of +5% or 1% of the numerical designation or value.
[0049] As used herein, "administer-, with respect to a targeting agent such as an antibody, antibody fragment, Fab fragment, or aptamer, means to deliver the agent to a subject's body via any known method suitable for antibody delivery. Specific modes of administration include, without limitation, intravenous, transdermal, subcutaneous, intraperitoneal, intrathecal and intra-tumoral administration. Exemplary administration methods for antibodies may be as substantially described in International Publication No. WO 2016/187514, incorporated by reference herein.
[0050] In addition, in this invention, antibodies may, for example, be formulated using one or more routinely used pharmaceutically acceptable carriers and excipients. Such carriers and excipients are well known to those skilled in the art. For example, injectable drug delivery systems include solutions, suspensions, gels, microspheres and polymeric injectables, and can include excipients such as solubility-altering agents (e.g., ethanol, propylene glycol and sucrose) and polymers (e.g., polycaprylactones and PLGA's).
[0051] As used herein, the term "antibody" includes, without limitation. (a) an immunoglobulin molecule including two heavy chains and two light chains and which recognizes an antigen; (b) polyclonal and monoclonal immunoglobulin molecules;
(c) monovalent and divalent fragments thereof, such as Fab, di-Fab, scFvs, diabodi es, minibodies, and nanobodies (sdAb); (d) naturally occurring and non-naturally occurring, such as wholly synthetic antibodies, IgG-Fc-silent, and chimeric; and (e) hi-specific and multi-specific forms thereof. Immunoglobulin molecules may derive from any of the commonly known classes, including but not limited to IgA, secretory IgA, IgG and IgM. IgG subclasses are also well known to those in the art and include, but are not limited to, human IgGl, IgG2, IgG3 and IgG4.
The N-terminus of each chain defines a -variable region" of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL) and variable heavy chain (VH) refer to these regions of light and heavy chains respectively.
Antibodies may be human, humanized or nonhuman. When a specific aspect of the presently disclosed invention refers to or recites an "antibody,- it is envisioned as referring to any of the full-length antibodies or fragments thereof disclosed herein, unless explicitly denoted otherwise.
[0052] A "humanized" antibody refers to an antibody in which some, most or all amino acids outside the CDR domains of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins. In one embodiment of a humanized form of an antibody, some, most or all of the amino acids outside the CDR domains have been replaced with amino acids from human immunoglobulins, whereas some, most or all amino acids within one or more CDR regions are unchanged. Small additions, deletions, insertions, substitutions or modifications of amino acids are permissible as long as they do not abrogate the ability of the antibody to bind to a particular antigen A "humanized" antibody retains an antigenic specificity similar to that of the original antibody.
[0053] A "chimeric antibody" refers to an antibody in which the variable regions are derived from one species and the constant regions are derived from another species, such as an antibody in which the variable regions are derived from a mouse antibody and the constant regions are derived from a human antibody.
[0054] A "complementarity-determining region", or "CDR", refers to amino acid sequences that, together, define the binding affinity and specificity of the variable region of a native immunoglobulin binding site. There are three CDRs in each of the light and heavy chains of an antibody.
[0055] A "framework region", or "FR", refers to amino acid sequences interposed between CDRs, typically conserved, that act as the scaffold between the CDRs.
100561 A "constant region" refers to the portion of an antibody molecule that is consistent for a class of antibodies and is defined by the type of light and heavy chains. For example, a light chain constant region can be of the kappa or lambda chain type and a heavy chain constant region can be of one of the five chain isotypes: alpha, delta, epsilon, gamma or mu. This constant region, in general, can confer effector functions exhibited by the antibodies.
Heavy chains of various subclasses (such as the IgG subclass of heavy chains) are mainly responsible for different effector functions.
[0057] As used herein, a HER3 targeting agent may, for example, be an antibody as defined herein, e.g., full length antibody, minibody, or nanobody, that binds to any available epitope of HER3, such as human HER3, with a high immunoreactivity.
[0058] As used herein, -Immunoreactivity" refers to a measure of the ability of an immunoglobulin to recognize and bind to a specific antigen. "Specific binding"
or "specifically binds" or "binds" refers to an antibody binding to an antigen or an epitope within the antigen with greater affinity than for other antigens, for example, within a relevant context such as within the body of a mammalian subject such as a human patient. An antibody, which may be embodied in or used in the various aspects of the invention, may for example bind to the antigen or the epitope within the antigen with an equilibrium dissociation constant (Ko) of about 1 x108 M or less, for example about lx 10' M or less, about 1 x10-10 M or less, about 1 x10-1-1 M or less, or about 1x10-12M or less, typically with the KD that is at least one hundred fold less than its Ko for binding to a nonspecific antigen (e.g., BSA, casein). The dissociation constant may be measured using standard procedures. Antibodies that specifically bind to the antigen or the epitope within the antigen may, however, have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca fascicularis (cynomolgus, cyno), Pan troglodytes (chimpanzee, chimp) or Callithrix jacchus (common marmoset, marmoset).
[0059] An "epitope" refers to the target molecule site (e.g., at least a portion of an antigen) that is capable of being recognized by, and bound by, a targeting agent such as an antibody, antibody fragment, Fab fragment, or aptamer. For a protein antigen, for example, this may refer to the region of the protein (i.e., amino acids, and particularly their side chains) that is bound by the antibody. Overlapping epitopes include at least one to five common amino acid residues. Methods of identifying epitopes of antibodies are known to those skilled in the art and include, for example, those described in Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1988).
[0060] Radiolabeled HER3 targeting agents as disclosed herein may be used to treat HER3-positive, i.e., HER3-expressing, cancers or precancerous conditions, such as solid tumors.
By "HER3-positive- or "HER3-expressing" it is meant that at least some of the cancer cells within a patient, such as within a tumor, express or over-express HER3.
[0061] As used herein, the terms "proliferative disorder" and "cancer" may be used interchangeably and may include, without limitation, a solid cancer (e.g., a tumor) and precancerous proliferative disorders. "Solid cancers" that may be treated by the various aspects of the invention and which may be HER3-positive include, without limitation, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, prostate cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, pediatric tumors, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, environmentally-induced cancers including those induced by asbestos Such cancers may be metastatic or non-metastatic.
[0062] According to certain aspects, the solid cancer which may be treated by the various aspects of the invention and which may be HER3-positive, may be breast cancer such as tamoxifen-sensitive breast cancer, tamoxifen-resistant breast cancer, HER2-positive breast cancer, HER2-negative breast cancer, or triple negative breast cancer (TNBC), gastric cancer, bladder cancer, cervical cancer, endometrial cancer, skin cancer such as melanoma, stomach cancer, testicular cancer, esophageal cancer, bronchioloalveolar cancer, prostate cancer such as castration resistant prostate cancer (CRPC), colorectal cancer, ovarian cancer, cervical epidermoid cancer, liver cancer such as hepatocellular carcinoma (HCC) or cholangiocarcinoma, pancreatic cancer, lung cancer such as non-small cell lung carcinoma (NSCLC), renal cancer, head and neck cancer such as head and neck squamous cell cancer, a carcinoma, a sarcoma, or any combination thereof Such cancers may be metastatic or non-metastatic.
[0063] According to certain aspects, the HER3 targeting agent may be labeled with a radioisotope/radionuclide. As used herein, a "radioisotope- or "radionuclide-can be an alpha-emitting isotope, a beta-emitting isotope, and/or a gamma-emitting isotope.
Exemplary radionuclides that may be used to label HER3 targeting agents or other targeting agents include the following: 1311, 1251, 1231, 90y, 177Lu, 186Re, 188Re, 89Sr, 153sm, 32p, 225Ac, 213Bi, 213po, 211At, 212Bi, 213Bi, 223Ra, 227-,, in 149Tb, 137cs, 212pb, 103pd, 134ce, 43sc, 44se, 47=-"c, 55CO, 60cu, 61cu, 62cu, 64cti, 67cti, 66Ga, kra 68Ga, 82Rb, 86Y, 87Y, 89Zr, 97Ru, 1o5Rh, io9pd, 1111n, 117msn, 149pm, 149Tb, 153sm, 177Lu, 199 == u, 201T1, and 203Pb. Methods for affixing a radioisotope to a protein such as an antibody or antibody fragment (i.e., "labeling" the protein with the radioisotope) are well known in the art. Specific compositions and methods for labeling are described, for example, in International Publication No. WO 2017/155937 and US Provisional Patent Application Nos.
63/042,651 filed December 9, 2019 and 63/119,093 filed November 30, 2020 titled "Compositions and methods for preparation of site-specific radioconjugates,-each of which is incorporated by reference herein. HER3 targeting agents and other targeting agents containing one or more cysteine residues, such as peptides, proteins, antibodies and protein antibody mimetics may, for example, be chemically conjugated to any of the chelator-bearing, such as DOTA-bearing, stable linkers disclosed in U.S. Patent 11,000,604 titled "Reagent for site-selective bioconjugation of proteins or antibodies" for radionuclide labeling.
[0064] According to certain aspects, the HER3 targeting agent may be an antibody, peptide, or small molecule radiolabeled with 225Ac ("225Ac-labeled"), and the effective amount may, for example, be at or below 50.0 pCi/kg (i.e., where the amount of 225AC
administered to the subject delivers a radiation dose of below 50.0 pCi per kilogram of subject's body weight).
According to certain aspects, when the HER3 targeting agent is 'Ac-labeled, the effective amount is below 50 pCi/kg, 40 IACi/kg, 30 pCi/kg, 20 CiIkg, 10 pCi/kg, 5 pCi/kg, 4 pCi/kg, 3 pCi/kg, 2 pCi/kg, 1 pCi/kg, or 0.5 pCi/kg. According to certain aspects, when the HER3 targeting agent is 225Ac-labeled, the effective amount is at least 0.05 pCi/kg, or 0.1 [iCi/kg, 0.2 pCi/kg, 0.3 uCi/kg, 0.4 Ci/kg, 0.5 pCi/kg, 1 pCi/kg, 2 pCi/kg, 3 pCi/kg, 4 1..iCi/kg, 5 pCi/kg, 6 pCi/kg, 7 pCi/kg, 8 pCi/kg, 9 pCi/kg, 10 pCi/kg, 12 pCi/kg, 14 pCi/kg, 15 pCi/kg, 16 pCi/kg, 18 pCi/kg, 20 pCi/kg, 30 pCi/kg, or 40 pCi/kg. According to certain aspects, the 225Ac-labeled antibody may be administered at a dose that includes any combination of upper and lower limits as described herein, such as from at least 0.1 pCi/kg to at or below 5 pCi/kg, or from at least 5 pCi/kg to at or below 20 pCi/kg.
[0065] According to certain aspects, the HER3 targeting agent may be an antibody, peptide, or small molecule that is 225Ac-labeled, and the effective amount may be at or below 2 mCi (i.e., wherein the 'Ac is administered to the subject in a non-weight-based dosage).
According to certain aspects, the effective dose of the 'Ac-labeled HER3 targeting agent may be below 1 mCi, such as 0.9 mCi, 0.8 mCi, 0.7 mCi, 0.6 mCi, 0.5 mCi, 0.4 mCi, 0.3 mCi, 0.2 mCi, 0.1 mCi, 90 pCi, 80 pCi, 70 pCi, 60 pCi, 50 pCi, 40 pCi, 30 pCi. 20 pCi,
[0044] The presently disclosed invention further provides methods for identifying, imaging and/or diagnosing ITER3-positive cancers in a subject. The presently disclosed invention further provides methods for identifying, imaging and/or diagnosing HER3-positive cancer in a subject, followed by treating those subjects according to any of the methods disclosed herein.
[0045] Definitions and Abbreviations [0046] The singular forms "a," "an," "the" and the like include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an"
antibody includes both a single antibody and a plurality of different antibodies.
100471 The words "comprising" and forms of the word -comprising" as well as the word "including" and forms of the word "including," as used in this description and in the claims, do not limit the inclusion of elements beyond what is referred to. Additionally, although throughout the present disclosure various aspects or elements thereof are described in terms of "including"
or "comprising,- corresponding aspects or elements thereof described in terms of "consisting essentially of' or -consisting of' are similarly disclosed. For example, while certain aspects of the invention have been described in terms of a method "including" or "comprising"
administering a radiolabeled targeting agent, corresponding methods instead reciting "consisting essentially of' or "consisting of' administering the radiolabeled target are also within the scope of said aspects and disclosed by this disclosure.
[0048] The term -about" when used in this disclosure in connection with a numerical designation or value, e.g., in describing temperature, time, amount, and concentration, including in the description of a range, indicates a variance of +10% and, within that larger variance, variances of +5% or 1% of the numerical designation or value.
[0049] As used herein, "administer-, with respect to a targeting agent such as an antibody, antibody fragment, Fab fragment, or aptamer, means to deliver the agent to a subject's body via any known method suitable for antibody delivery. Specific modes of administration include, without limitation, intravenous, transdermal, subcutaneous, intraperitoneal, intrathecal and intra-tumoral administration. Exemplary administration methods for antibodies may be as substantially described in International Publication No. WO 2016/187514, incorporated by reference herein.
[0050] In addition, in this invention, antibodies may, for example, be formulated using one or more routinely used pharmaceutically acceptable carriers and excipients. Such carriers and excipients are well known to those skilled in the art. For example, injectable drug delivery systems include solutions, suspensions, gels, microspheres and polymeric injectables, and can include excipients such as solubility-altering agents (e.g., ethanol, propylene glycol and sucrose) and polymers (e.g., polycaprylactones and PLGA's).
[0051] As used herein, the term "antibody" includes, without limitation. (a) an immunoglobulin molecule including two heavy chains and two light chains and which recognizes an antigen; (b) polyclonal and monoclonal immunoglobulin molecules;
(c) monovalent and divalent fragments thereof, such as Fab, di-Fab, scFvs, diabodi es, minibodies, and nanobodies (sdAb); (d) naturally occurring and non-naturally occurring, such as wholly synthetic antibodies, IgG-Fc-silent, and chimeric; and (e) hi-specific and multi-specific forms thereof. Immunoglobulin molecules may derive from any of the commonly known classes, including but not limited to IgA, secretory IgA, IgG and IgM. IgG subclasses are also well known to those in the art and include, but are not limited to, human IgGl, IgG2, IgG3 and IgG4.
The N-terminus of each chain defines a -variable region" of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL) and variable heavy chain (VH) refer to these regions of light and heavy chains respectively.
Antibodies may be human, humanized or nonhuman. When a specific aspect of the presently disclosed invention refers to or recites an "antibody,- it is envisioned as referring to any of the full-length antibodies or fragments thereof disclosed herein, unless explicitly denoted otherwise.
[0052] A "humanized" antibody refers to an antibody in which some, most or all amino acids outside the CDR domains of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins. In one embodiment of a humanized form of an antibody, some, most or all of the amino acids outside the CDR domains have been replaced with amino acids from human immunoglobulins, whereas some, most or all amino acids within one or more CDR regions are unchanged. Small additions, deletions, insertions, substitutions or modifications of amino acids are permissible as long as they do not abrogate the ability of the antibody to bind to a particular antigen A "humanized" antibody retains an antigenic specificity similar to that of the original antibody.
[0053] A "chimeric antibody" refers to an antibody in which the variable regions are derived from one species and the constant regions are derived from another species, such as an antibody in which the variable regions are derived from a mouse antibody and the constant regions are derived from a human antibody.
[0054] A "complementarity-determining region", or "CDR", refers to amino acid sequences that, together, define the binding affinity and specificity of the variable region of a native immunoglobulin binding site. There are three CDRs in each of the light and heavy chains of an antibody.
[0055] A "framework region", or "FR", refers to amino acid sequences interposed between CDRs, typically conserved, that act as the scaffold between the CDRs.
100561 A "constant region" refers to the portion of an antibody molecule that is consistent for a class of antibodies and is defined by the type of light and heavy chains. For example, a light chain constant region can be of the kappa or lambda chain type and a heavy chain constant region can be of one of the five chain isotypes: alpha, delta, epsilon, gamma or mu. This constant region, in general, can confer effector functions exhibited by the antibodies.
Heavy chains of various subclasses (such as the IgG subclass of heavy chains) are mainly responsible for different effector functions.
[0057] As used herein, a HER3 targeting agent may, for example, be an antibody as defined herein, e.g., full length antibody, minibody, or nanobody, that binds to any available epitope of HER3, such as human HER3, with a high immunoreactivity.
[0058] As used herein, -Immunoreactivity" refers to a measure of the ability of an immunoglobulin to recognize and bind to a specific antigen. "Specific binding"
or "specifically binds" or "binds" refers to an antibody binding to an antigen or an epitope within the antigen with greater affinity than for other antigens, for example, within a relevant context such as within the body of a mammalian subject such as a human patient. An antibody, which may be embodied in or used in the various aspects of the invention, may for example bind to the antigen or the epitope within the antigen with an equilibrium dissociation constant (Ko) of about 1 x108 M or less, for example about lx 10' M or less, about 1 x10-10 M or less, about 1 x10-1-1 M or less, or about 1x10-12M or less, typically with the KD that is at least one hundred fold less than its Ko for binding to a nonspecific antigen (e.g., BSA, casein). The dissociation constant may be measured using standard procedures. Antibodies that specifically bind to the antigen or the epitope within the antigen may, however, have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca fascicularis (cynomolgus, cyno), Pan troglodytes (chimpanzee, chimp) or Callithrix jacchus (common marmoset, marmoset).
[0059] An "epitope" refers to the target molecule site (e.g., at least a portion of an antigen) that is capable of being recognized by, and bound by, a targeting agent such as an antibody, antibody fragment, Fab fragment, or aptamer. For a protein antigen, for example, this may refer to the region of the protein (i.e., amino acids, and particularly their side chains) that is bound by the antibody. Overlapping epitopes include at least one to five common amino acid residues. Methods of identifying epitopes of antibodies are known to those skilled in the art and include, for example, those described in Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1988).
[0060] Radiolabeled HER3 targeting agents as disclosed herein may be used to treat HER3-positive, i.e., HER3-expressing, cancers or precancerous conditions, such as solid tumors.
By "HER3-positive- or "HER3-expressing" it is meant that at least some of the cancer cells within a patient, such as within a tumor, express or over-express HER3.
[0061] As used herein, the terms "proliferative disorder" and "cancer" may be used interchangeably and may include, without limitation, a solid cancer (e.g., a tumor) and precancerous proliferative disorders. "Solid cancers" that may be treated by the various aspects of the invention and which may be HER3-positive include, without limitation, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, prostate cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, pediatric tumors, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, environmentally-induced cancers including those induced by asbestos Such cancers may be metastatic or non-metastatic.
[0062] According to certain aspects, the solid cancer which may be treated by the various aspects of the invention and which may be HER3-positive, may be breast cancer such as tamoxifen-sensitive breast cancer, tamoxifen-resistant breast cancer, HER2-positive breast cancer, HER2-negative breast cancer, or triple negative breast cancer (TNBC), gastric cancer, bladder cancer, cervical cancer, endometrial cancer, skin cancer such as melanoma, stomach cancer, testicular cancer, esophageal cancer, bronchioloalveolar cancer, prostate cancer such as castration resistant prostate cancer (CRPC), colorectal cancer, ovarian cancer, cervical epidermoid cancer, liver cancer such as hepatocellular carcinoma (HCC) or cholangiocarcinoma, pancreatic cancer, lung cancer such as non-small cell lung carcinoma (NSCLC), renal cancer, head and neck cancer such as head and neck squamous cell cancer, a carcinoma, a sarcoma, or any combination thereof Such cancers may be metastatic or non-metastatic.
[0063] According to certain aspects, the HER3 targeting agent may be labeled with a radioisotope/radionuclide. As used herein, a "radioisotope- or "radionuclide-can be an alpha-emitting isotope, a beta-emitting isotope, and/or a gamma-emitting isotope.
Exemplary radionuclides that may be used to label HER3 targeting agents or other targeting agents include the following: 1311, 1251, 1231, 90y, 177Lu, 186Re, 188Re, 89Sr, 153sm, 32p, 225Ac, 213Bi, 213po, 211At, 212Bi, 213Bi, 223Ra, 227-,, in 149Tb, 137cs, 212pb, 103pd, 134ce, 43sc, 44se, 47=-"c, 55CO, 60cu, 61cu, 62cu, 64cti, 67cti, 66Ga, kra 68Ga, 82Rb, 86Y, 87Y, 89Zr, 97Ru, 1o5Rh, io9pd, 1111n, 117msn, 149pm, 149Tb, 153sm, 177Lu, 199 == u, 201T1, and 203Pb. Methods for affixing a radioisotope to a protein such as an antibody or antibody fragment (i.e., "labeling" the protein with the radioisotope) are well known in the art. Specific compositions and methods for labeling are described, for example, in International Publication No. WO 2017/155937 and US Provisional Patent Application Nos.
63/042,651 filed December 9, 2019 and 63/119,093 filed November 30, 2020 titled "Compositions and methods for preparation of site-specific radioconjugates,-each of which is incorporated by reference herein. HER3 targeting agents and other targeting agents containing one or more cysteine residues, such as peptides, proteins, antibodies and protein antibody mimetics may, for example, be chemically conjugated to any of the chelator-bearing, such as DOTA-bearing, stable linkers disclosed in U.S. Patent 11,000,604 titled "Reagent for site-selective bioconjugation of proteins or antibodies" for radionuclide labeling.
[0064] According to certain aspects, the HER3 targeting agent may be an antibody, peptide, or small molecule radiolabeled with 225Ac ("225Ac-labeled"), and the effective amount may, for example, be at or below 50.0 pCi/kg (i.e., where the amount of 225AC
administered to the subject delivers a radiation dose of below 50.0 pCi per kilogram of subject's body weight).
According to certain aspects, when the HER3 targeting agent is 'Ac-labeled, the effective amount is below 50 pCi/kg, 40 IACi/kg, 30 pCi/kg, 20 CiIkg, 10 pCi/kg, 5 pCi/kg, 4 pCi/kg, 3 pCi/kg, 2 pCi/kg, 1 pCi/kg, or 0.5 pCi/kg. According to certain aspects, when the HER3 targeting agent is 225Ac-labeled, the effective amount is at least 0.05 pCi/kg, or 0.1 [iCi/kg, 0.2 pCi/kg, 0.3 uCi/kg, 0.4 Ci/kg, 0.5 pCi/kg, 1 pCi/kg, 2 pCi/kg, 3 pCi/kg, 4 1..iCi/kg, 5 pCi/kg, 6 pCi/kg, 7 pCi/kg, 8 pCi/kg, 9 pCi/kg, 10 pCi/kg, 12 pCi/kg, 14 pCi/kg, 15 pCi/kg, 16 pCi/kg, 18 pCi/kg, 20 pCi/kg, 30 pCi/kg, or 40 pCi/kg. According to certain aspects, the 225Ac-labeled antibody may be administered at a dose that includes any combination of upper and lower limits as described herein, such as from at least 0.1 pCi/kg to at or below 5 pCi/kg, or from at least 5 pCi/kg to at or below 20 pCi/kg.
[0065] According to certain aspects, the HER3 targeting agent may be an antibody, peptide, or small molecule that is 225Ac-labeled, and the effective amount may be at or below 2 mCi (i.e., wherein the 'Ac is administered to the subject in a non-weight-based dosage).
According to certain aspects, the effective dose of the 'Ac-labeled HER3 targeting agent may be below 1 mCi, such as 0.9 mCi, 0.8 mCi, 0.7 mCi, 0.6 mCi, 0.5 mCi, 0.4 mCi, 0.3 mCi, 0.2 mCi, 0.1 mCi, 90 pCi, 80 pCi, 70 pCi, 60 pCi, 50 pCi, 40 pCi, 30 pCi. 20 pCi,
10 pCi, or 5 pCi.
The effective amount of 225Ac-labeled HER3 targeting agent may be at least 2 pCi, such as at least 5 pCi, 10 pCi, 20 pCi, 30 pCi, 40 pCi, 50 pCi, 60 pCi, 70 pCi, 80 pCi, 90 pCi, 100 pCi, 200 pCi, 300 pCi, 400 pCi, 500 pCi, 600 pCi, 700 pCi, 800 pCi, 900 pCi, 1 mCi, 1.1 mCi, 1,2 mCi, 1.3 mCi, 1.4 mCi, or 1.5 mCi. According to certain aspects, the 225Ac-labeled HER3 targeting agent may be administered at a dose that includes any combination of upper and lower limits as described herein, such as from at least 2 tiCi to at or below 1mCi, or from at least 2 pCi to at or below 250 pCi, or from 75 pCi to at or below 400 [0066] According to certain aspects, the 225Ac-labeled HER3 targeting agent includes a single dose that delivers less than 12Gy, or less than 8 Gy, or less than 6 Gy, or less than 4 Gy, or less than 2 Gy, such as doses of 2 Gy to 8 Gy, to the subject, such as predominantly to the targeted solid tumor.
[00671 According to certain aspects, the HER3 targeting agent may be an antibody, peptide, or small molecule radiolabeled with 177Lu ("177Lu-labeled"), and the effective amount may be, for example, below 1 mCi/kg (i.e., where the amount of 177Lu-labeled antibody administered to the subject delivers a radiation dose of below 1000 nCi per kilogram of subject's body weight). According to certain aspects, when the antibody is 'Lu-labeled, the effective amount is below 900 pCi/kg, 800 nCi/kg, 700 pCi/kg, 600 p,Ci/kg, 500 pCi/kg, 400 pCi/kg, 300 litCi/kg, 200 1.1,Ci/kg, 150 laCi/kg, 100 nCi/kg, 80 nCi/kg, 60 pCi/kg, 50 IJ,Ci/kg, 40 IJ,Ci/kg, 30 pCi/kg, 20 pCi/kg, 10 [1,Ci/kg, 5 nCi/kg, or 1 nCi/kg. According to certain aspects, the effective amount of the 177Lu-labeled antibody is at least 1 pCi/kg, 2.5 pCi/kg, 5 pCi/kg, 10 !..iCi/kg, 20 pCi/kg, 30 pCi/kg, 40 pCi/kg, 50 pCi/kg, 60 pCi/kg, 70 pCi/kg, 80 pCi/kg, 90 pCi/kg, 100 pCi/kg, 150 pCi/kg, 200 pCi/kg, 250 pCi/kg, 300 pCi/kg, 350 pCi/kg, 400 pCi/kg or 450 pCi/kg.
According to certain aspects, an 177Lu-labeled antibody may be administered at a dose that includes any combination of upper and lower limits as described herein, such as from at least 5 mCi/kg to at or below 50 pCi/kg, or from at least 50 mCi/kg to at or below 500 pCi/kg.
[00681 According to certain aspects, the HER3 targeting agent may be an antibody that is 177Lu-labeled, and the effective amount may be below 45 mCi, such as below 40 mCi, 30 mCi, mCi, 10 mCi, 5 mCi, 3.0 mCi, 2.0 mCi, 1.0 mCi, 800 põCi, 600 pCi, 400 pCi, 200 nCi, 100 pCi, or 50 pCi. The effective amount of 177Lu-labeled HER3 targeting agent may be at least 10 pCi, such as at least 25 pCi, 50 nCi, 100 pCi, 200 pCi, 300 pCi, 400 pCi, 500 pCi, 600 pCi, 700 pCi, 800 pCi, 900 pCi, 1 mCi, 2 mCi, 3 mCi, 4 mCi, 5 mCi, 10 mCi, 15 mCi, 20 mCi, 25 mCi, 30 mCi. According to certain aspects, an 177Lu-labeled antibody may be administered at a dose that includes any combination of upper and lower limits as described herein, such as from at least 10 mCi to at or below 30 mCi, or from at least 100 pCi to at or below 3 mCi, or from 3 mCi to at or below 30 mCi.
[00691 According to certain aspects, the HER3 targeting agent may be an antibody, peptide, or small molecule radiolabeled with 1311 ("1_311-labeler), and the effective amount may be below, for example, 1200 mCi (i.e., where the amount of 131I administered to the subject delivers a total body radiation dose of below 1200 mCi in a non-weight-based dose). According to certain aspects, the effective amount of the 131I-labeled targeting agent may be below 1100 mCi, below 1000 mCi, below 900 mCi, below 800 mCi, below 700 mCi, below 600 mCi, below 500 mCi, below 400 mCi, below 300 mCi, below 200 mCi, below 150 mCi, or below 100 mCi.
According to certain aspects, the effective amount of the 'I-labeled targeting agent may be below 200 mCi, such as below 190 mCi, 180 mCi, 170 mCi, 160 mCi, 150 mCi, 140 mCi, 130 mCi, 120 mCi, 110 mCi, 100 mCi, 90 mCi, 80 mCi, 70 mCi, 60 mCi, or 50 mCi.
According to certain aspects, the effective amount of the 134-labeled targeting agent may be at least 1 mCi, such as at least 2 mCi, 3 mCi, 4 mCi, 5 mCi, 6 mCi, 7 mCi, 8 mCi, 9 mCi, 10 mCi, 20 mCi, 30 mCi, 40 mCi, 50 mCi, 60 mCi, 70 mCi, 80 mCi, 90 mCi, 100 mCi, 110 mCi, 120 mCi, 130 mCi, 140 mCi, 150 mCi, 160 mCi, 170 mCi, 180 mCi, 190 mCi, 200 mCi, 250 mCi, 300 mCi, 350 mCi, 400 mCi, 450 mCi, 500 mCi. According to certain aspects, an "II-labeled targeting agent may be administered at a dose that includes any combination of upper and lower limits as described herein, such as from at least 1 mCi to at or below 100 mCi, or at least 10 mCi to at or below 200 mCi.
[0070] While select radionuclides are discussed in detail herein, any, such as any disclosed herein, may be used for radiolabeled targeting agents, such as a radiolabeled HER3 targeting agent as disclosed herein.
[00711 As used herein, a composition including a HER3 targeting agent includes a -patient specific composition" that includes both a radionuclide labeled portion and an unlabeled portion. According to certain aspects of the present invention, when the HER3 targeting agent is labeled with a radioisotope, the majority of the targeting agent (antibody, antibody fragment, etc.) administered to a patient may consist of unlabeled targeting agent, with the minority being the radiolabeled targeting agent. The ratio of labeled to non-labeled targeting agent can be adjusted using known methods. According to certain aspects of the present invention, the patient specific composition may include the HER3 targeting agent in a ratio of labeled : unlabeled HER3 targeting agent of from about 0.01:10 to 1:1, such as 0.1:10 to 1:1 labeled: unlabeled.
[0072] Accordingly to certain aspects of the present invention, the HER3 targeting agent may be provided in a total protein or peptide amount of up to 100mg, such as up to 60 mg, such as 5mg to 45mg, or a total protein amount of from 0.001 mg/kg patient weight to 3.0 mg/kg patient weight, such as from 0.005 mg/kg patient weight to 2.0 mg/kg patient weight, or from 0.01 mg/kg patient weight to 1 mg/kg patient weight, or from 0.1 mg/kg patient weight to 0.6 mg/kg patient weight, or 0.3 mg/kg patient weight, or 0.4 mg/kg patient weight, or 0.5 mg/kg patient weight, or 0.6 mg/kg patient weight.
[0073] The inventive combination of a radiolabeled fraction and an unlabeled fraction of the antibody or other targeting agent allows the composition to be tailored to a specific patient, wherein each of the radiation dose and the protein dose of the antibody or other targeting agent are personalized to that patient based on at least one patient-specific parameter. As such, each vial of the composition may be made for a specific patient, where the entire content of the vial is delivered to that patient in a single dose. When a treatment regime calls for multiple doses, each dose may be formulated as a patient specific dose in a vial to be administered to the patient as a "single dose" (i.e., full contents of the vial administered at one time). The subsequent dose may be formulated in a similar manner, such that each dose in the regime provides a patient specific dose in a single dose container. One of the advantages of such a composition is that there will be no left-over radiation that would need to be discarded or handled by the medical personnel, e.g., no dilution, or other manipulation to obtain a dose for the patient. When provided in a single dose container, the container may simply be placed in-line in an infusion tubing set for infusion to the patient Moreover, the volume can be standardized so that there is a greatly reduced possibility of medical error (i.e., delivery of an incorrect dose, as the entire volume of the composition is to be administered in one infusion).
[0074] Thus, according to certain aspects, the HER3 targeting agent may be provided as a single dose composition which may be tailored to a specific patient, wherein the amount of radiolabeled and unlabeled 1-lER3 targeting agent in the composition may depend on one or more of a patient weight, age, gender, disease state and/or health status, such as detailed in International Publication No. WO 2016/187514 and U.S. Patent No. 10,736,975.
According to certain aspects, the HER3 targeting agent may be provided as a multi-dose therapeutic, wherein each dose in the treatment regime is provided as a patient specific composition The patient-specific composition includes radiolabeled and unlabeled HER3 targeting agents, wherein the amounts of each depend on one or more of patient weight, age, gender, disease state, and/or health status.
[0075] As used herein, the terms "subject" and "patient" are interchangeable and include, without limitation, a mammal such as a human, a non-human primate, a dog, a cat, a horse, a sheep, a goat, a cow, a rabbit, a pig, a rat and a mouse. Where the subject is human, the subject may be of any age. For example, the subject can be 60 years or older, 65 or older, 70 or older, 75 or older, 80 or older, 85 or older, or 90 or older. Alternatively, the subject can be 50 years or younger, 45 or younger, 40 or younger, 35 or younger, 30 or younger, 25 or younger, or 20 or younger. For a human subject afflicted with cancer, the subject can be newly diagnosed, or relapsed and/or refractory, or in remission.
[0076] As used herein, "treating" a subject afflicted with a cancer shall include, without limitation, (i) slowing, stopping or reversing the cancer's progression, (ii) slowing, stopping or reversing the progression of the cancer's symptoms, (iii) reducing the likelihood of the cancer's recurrence, and/or (iv) reducing the likelihood that the cancer's symptoms will recur. According to certain preferred aspects, treating a subject afflicted with a cancer means (i) reversing the cancer's progression, ideally to the point of eliminating the cancer, and/or (ii) reversing the progression of the cancer's symptoms, ideally to the point of eliminating the symptoms, and/or (iii) reducing or eliminating the likelihood of relapse (i.e., consolidation, which ideally results in the destruction of any remaining cancer cells).
[0077] "Chemotherapeutic-, in the context of this invention, shall mean a chemical compound which inhibits or kills growing cells and which can be used or is approved for use in the treatment of cancer. Exemplary chemotherapeutic agents include cytostatic agents which prevent, disturb, disrupt or delay cell division at the level of nuclear division or cell plasma division. Such agents may stabilize microtubules, such as taxanes, in particular docetaxel or paclitaxel, and epothilones, in particular epothilone A, B, C, D, E, and F, or may destabilize microtubules such as vinca alkaloids, in particular vinblastine, vincristine, vindesine, vinflunine, and vinorelbine. Exemplary chemotherapeutics also include radiosensitizers that may synergize with the radiolabeled 1-IER3, such as temozolomide, cisplatin, and/or fluorouracil.
[0078] "Therapeutically effective amount" or "effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. A
therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic or combination of therapeutics include, for example, improved well-being of the patient, reduction in a tumor burden, arrested or slowed growth of a tumor, and/or absence of metastasis of cancer cells to other locations in the body. According to certain aspects, "therapeutically effective amount" or "effective amount" refers to an amount of the radiolabeled HER3 targeting agent that may deplete or cause a reduction in the overall number of cells expressing HER3 and/or that may inhibit growth of cells expressing HER3, when used alone or in combination or conjunction with other agents and/treatment modalities.
[0079] As used herein, "depleting", with respect to cells expressing HER3, shall mean to lower the population of at least one type of cells that express or overexpress HER3 (e.g., HER3-positive cells in a solid tumor or circulating in a subject's blood).
According to certain aspects of this invention, a decrease is determined by comparison of the numbers of HER3-positive cells in the subject's blood or in a tissue biopsy, such as from the solid tumor, before and after initiation of treatment with the HER3 targeting agent. As such, and by way of example, a subject's HER3-positive cells may be considered to be depleted if the population is lowered, such as by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99%.
100801 -Inhibits growth" refers to a measurable decrease or delay in the growth of a malignant cell or tissue (e.g., tumor) in vitro or in vivo when contacted with a therapeutic or a combination of therapeutics or drugs, when compared to the decrease or delay in the growth of the same cells or tissue in the absence of the therapeutic or the combination of therapeutic drugs.
Inhibition of growth of a malignant cell or tissue in vitro or in vivo may be at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%.
[0081] The term "immune checkpoint therapy" refers to a molecule capable of modulating the function of an immune checkpoint protein in a positive or negative way in the furtherance of immune response against cancer cells. The term "immune checkpoint" refers to a protein directly or indirectly involved in an immune pathway that under normal physiological conditions acts to prevent uncontrolled immune reactions and thus for the maintenance of self-tolerance and/or tissue protection.
[00821 In the context of the present invention, an immune checkpoint therapy encompasses therapies such as antibodies capable of down-regulating at least partially the function of an inhibitory immune checkpoint (antagonist) and/or up-regulating at least partially the function of a stimulatory immune checkpoint (agonist). As example, an immune checkpoint therapy may refer to an antibody against an immune checkpoint inhibitor (ICI) that may be upregulated in certain cancers, and thus may inhibit the function of the ICI.
[0083] The term "DDRi" refers to an inhibitor of a DNA damage response pathway protein, of which a PARPi is an example. The term "PARPi" refers to an inhibitor of poly(ADP-ribose) polymerase. In the context of the present invention, the term PARPi encompasses molecules that may bind to and inhibitor the function of poly(ADP-ribose) polymerase, such as antibodies, peptides, or small molecules.
[00841 The term "CD47 blockade" refers to an agent that prevents CD47 binding to SIRPa, such as blocking agents that bind to either of CD47 or SIRPa, or those that modulate expression of CD47 or SIRPa, or those that otherwise inhibit the CD47/SIRPct axis. Without limitation, CD47 blockades encompass at least antibodies that bind to CD47 such as magrolimab, lemzoparlimab, and A0-176, SIRPa fusion proteins such as TTI-621 and TTI-622, agents that modulate the expression of CD47 and/or SIRPa, such as phosphorodiamidate morpholino oligomers (PMO) that block translation of CD47, and small molecule agents such as RRx -001.
100851 As used herein, administering to a subject one or more additional therapies, such as one or more of an immune checkpoint therapy and/or DDRi and/or CD47 blockade and/or radiosensitizer "in conjunction with" a HER3 targeting agent means administering the additional therapy before, during and/or after administration of the HER3 targeting agent. This administration includes, without limitation, the following scenarios: (i) the additional therapy is administered first, and the HER3 targeting agent is administered second; (ii) the additional therapy is administered concurrently with the HER3 targeting agent (e.g., the DDRi is administered orally once per day for n days, and the HER3 targeting agent is administered intravenously in a single dose on one of days 2 through n-1 of the DDRi regimen); (iii) the additional therapy is administered concurrently with the HER3 targeting agent (e.g., the DDRi is administered orally for a duration of greater than one month, such as orally once per day for 35 days, 42 days, 49 days, or a longer period during which the cancer being treated does not progress and during which the DDRi does not cause unacceptable toxicity, and the HER3 targeting agent is administered intravenously in a single dose on a day within the first month of the DDRi regimen); and (iv) the HER3 targeting agent is administered first (e.g., intravenously in a single dose or a plurality of doses over a period of weeks), and the additional therapy is administered second (e.g., the DDRi is administered orally once per day for 21 days, 28 days, 35 days, 42 days, 49 days, or a longer period during which the cancer being treated does not progress and during which the DDRi does not cause unacceptable toxicity).
Additional peimutations that would be obvious to one of skill in the art are possible and within the scope of the presently claimed invention.
[0086] An "article of manufacture" indicates a package containing materials useful for the treatment, prevention and/or diagnosis of the disorders described herein.
The article of manufacture may include a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc.
The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition which is by itself or combined with another composition effective for treating, preventing and/or diagnosing the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition may be a radi olab el ed HER3 targeting agent according to aspects of the presently disclosed invention.
100871 A "label" or "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and/or warnings concerning the use of such therapeutic products As used herein, a label may indicate that the composition is used for treating a HER3-positive cancer and may optionally indicate administration routes and/or methods. Moreover, the article of manufacture may include (a) a first container with a composition contained therein, wherein the composition includes FIER3 targeting agent; and (b) a second container with a composition contained therein, wherein the composition includes a further cytotoxic or otherwise therapeutic agent according to aspects of the presently disclosed invention. Alternatively, or additionally, the article of manufacture may further include a second (or third) container including a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
[0088] Throughout this application, various patents, patent applications and other publications are cited, each of which is hereby incorporated by reference in its entirety.
[0089] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing described herein, suitable methods and materials are described below.
[0090] EXPERIMENTAL RESULTS
[00911 An anti-HER3 IgG monoclonal antibody consisting of heavy chain SEQ ID
NO:77 and light chain SEQ ID NO:78 was prepared, conjugated to the chelator DOTA using p-SCN-Bn-DOTA and radiolabeled via chelation with Actinium-225 for further investigation as described below in connection with FIGS 3-11.
[00921 FIG. 3 shows ELISA assay binding characteristics of an Ac225 labeled DOTA-conjugated anti-HER3 monoclonal antibody ("HER3-ARC") versus the unmodified anti-HER3 antibody and a non-specific antibody (IgG), demonstrating that the modifications do not materially affect immune reactivity to HER3.
[0093] The binding properties of 225Ac-HER3-ARC were evaluated by ELISA. A 96 well plate was coated with human recombinant HER3 overnight following by incubation of serial dilutions (0 - 100 jig/m1) of anti-HER3, 225Ac-HER3-ARC and IgG
(immunoglobulin 1, nonpecific IgG1 control) for lh at room temperature. A secondary antibody (Goat Anti-human IgG F(ab')20-HRP) was added and incubated for 30 min on ice followed by color development using HC1 1M for 10 min. The sample absorbance was measured at 450nm. 225Ac-showed similar binding properties to those of the native antibody by ELISA
(HER3-ARC: ECso = 0.0017 lug/nil, HER3 EC50 = 0 0022 litg/m1).
[0094] FIG. 4 is a graph showing the results of flow cytometry assays examining the binding of the 225Ac-HER3-ARC, the unmodified anti-HER3 mAb, non-specific antibody control (IgG), and secondary antibody only control to HER3-positive NCI-H1975 cells (human lung adenocarcinoma, NSCLC) and BxPC-3 cells (human pancreatic adenocarcinoma).
[0095] The binding properties of 225Ac-HER3-ARC were evaluated by flow cytometry in HER3+ cells (NCI-H1975 and BxPC3). Solutions (100 gimp of anti-HER3, 225Ac-ARC and IgG (immunoglobulin 1, nonspecific IgG1) were added to HER+ cells and incubated for lh at room temperature. A PE labeled secondary antibody was added and incubated for 30 min on ice. Sample fluorescence was measured using a flow cytometer. The binding properties of 225Ac-HER3-ARC to fIER3+ positive cell lines resembled those of the unmodified anti-HER3 mAb.
[0096] FIG. 5 is a graph showing the in vitro cytotoxic effect of 225Ac-HER3-ARC to HER3-positive cell line NCI-H1975 as a function of radiation dose.
[00971 The cytotoxic effects of 225Ac-HER3-ARC to HER3+ cell line NCI-H1975 were evaluated in a colorimetric assay using CellTiter 96 AQueous Non-Radioactive Cell Proliferation Assay (MTS). NCI-H1975 cells were incubated with 225Ac-HER3-ARC
for 24h at 37 C. Unbound 225Ac-HER3-ARC was then removed, and cells were cultured for 72h at 37 C.
Absorbance at 490 nm was measured and % of cell viability calculated. 225Ac-showed potent in vitro cytotoxicity against HER3+ cell line NCI-H1975.
100981 FIG. 6A is a graph showing that 225Ac-FEER3-ARC upregulates cell surface calreticulin (CRT) in NCI-H1975 cells and FIG. 6B is a graph showing that 225Ac-HER3-ARC
upregulates CD47 on NCI-H1975 cells.
[0099] The effect of 225Ac-HER3-ARC on cell surface expression of calreticulin (CRT) and CD47 by HER3+ cell line NC1-H1975 was examined using flow cytometry. Cells were treated with 225Ac-HER3-ARC (100 nCi/m1) or PBS (control) for 72h. Following treatment, cells were stained for CRT and CD47. The results demonstrate that each of CRT
(FIG. 6A) and CD47 (FIG. 6B) is upregulated by 225Ac-HER3-ARC in NCI-H1975 cells.
[0100] FIG. 7A is a graph showing results of a phagocytosis assay demonstrating that the combination of 225Ac-HER3-ARC and an anti-CD47 blocking antibody enhanced phagocytosis of BxPC-3 cells versus either treatment alone. FIG. 7B is a graph showing results of a phagocytosis assay demonstrating that the combination of 225Ac-HER3-ARC and an anti-CD47 blocking antibody enhanced phagocytosis of NCI-H1975 cells versus either treatment alone.
The same key applies for FIGS. 7A and 7B.
[0101] The effect of combining 225Ac-HER3-ARC and anti-CD47 on phagocytosis in vitro was evaluated by flow cytometry. BxPC-3 (FIG. 7A) and NCI-H1975 (FIG.
7B) cells were seeded in 6-well plates 24hr prior to a 24hr incubation at 37 C with 225Ac-HER3-ARC.
Following 225Ac-HER3-ARC treatment, cells were cultured for 72hr at 37 C.
[0102] BxPC-3 and NCI-H1975 cells were stained with Vybrant DiD cell-labeling solution and treated with anti-human CD47 (Bio X Cell, Cat#BE0019) and mouse IgG1 isotype control (Bio X Cell, Cat#BE0083) for ihr at 37 C. Human macrophages were stained with Vybrant Di0 cell-labeling solution. Labeled human macrophages and target cells were cocultured for 2h at 37 C. Phagocytosis was assessed by evaluating the dual labeled cells (DiD+/Di0+).
[0103] FIG. 8 is graph showing the effects on tumor growth, in a human tumor (NCI-H1975 cell) mouse xenograft model, of a 225Ac-HER3-ARC at different radiation doses (100 nCi, 200 nCi, 400 nCi, 600 nCi) alone and at 200 nCi in combination with an anti-CD47 blocking antibody, of unlabeled anti-HER3 mAb, of anti-CD47 blocking antibody alone, and of vehicle-only control. Notably, tumor growth was almost entirely suppressed by 225Ac-HER-ARC at each of radiation doses 200 nCi, 400 nCi, 600 nCi and by the combination of 225Ac-HER-ARC (200 nCi) with the anti-CD47 mAb.
[0104] FIG. 9 is a graph showing body weight over time for the subjects of the experiment described in FIG. 8.
[0105] FIG. 10 is a graph showing the probability of survival over time for the experimental group subjects of the experiment described in FIG. 8.
[0106] Tumor xenograft studies examining the effect of HER2-ARC treatment alone and in combination with CD47 blockade on HER2-positive tumor growth were also performed.
Anti-HER2 mAb Trastuzumab was chemically conjugated to DOTA using p-SCN-Bn-DOTA
and labeled, via chelation, with either Actinium-225 or Lutetium-177 for use in these experiments.
[0107] FIG. 11 is a graph showing the comparative effects on tumor growth of vehicle only (control), magrolimab alone (10 mg/kg), 225Ac-trastuzumab alone (0.025 p.Ci/animal), and the combination of magrolimab (10 mg/kg) and 225Ac-trastuzumab (0.025 uCi/animal), in an NGS mouse xenograft model using the HER2-positive SK-0V3 human ovarian cancer cell line.
Each cohort consisted of eight animals.
[0108] FIG. 12 is a graph showing the comparative effects on tumor growth of vehicle only (control), magrolimab alone (10 mg/kg), 177Lu-trastuzumab alone (25 uCi/animal), and the combination of magrolimab (10 mg/kg) and 177Lu-trastuzumab (25 [Xi/animal), in an NGS
mouse xenograft model using the HER2-positive SK-0V3 human ovarian cancer cell line. Each cohort consisted of eight animals.
[0109] ASPECTS OF THE INVENTION
[0110] It is well documented in both preclinical and clinical studies that levels of HER3 can become downregulated following administration of a HER3 -targeting antibody (Mi shra, 2018). In preclini cal models with lumretuzumab, there was a dose-dependent (1-10mg/kg) downregulation of HER3 as measured by both immunohistochemistry and Western blotting (Maneses-Lorenta, 2015; Mirshberger, 2013) The lowest dose of lumretuzumab (0.3 mg/kg) did not result in IAER3 target downregulation (Maneses-Lorenta, 2015), and these low levels of lumretuzumab (0.1mg/kg and 0.3 mg/kg) were ineffective at controlling HER3-expressing tumors (Mirshberger, 2013). In clinical studies with lumretuzumab, downregulation of surface HER3 was observed in serial tumor biopsies in 92% of patients across all dose levels tested (100-2000mg; Meulendijks, 2016). Additionally, a decrease in total HER3 levels was observed in three out of five paired tumor biopsy samples in patients treated with the HER3-targeting antibody L.TM716 at 40 mg/kg (Reynolds, 2017).
[inn] While the internalization and degradation of HER3 may be beneficial to reduce phosphorylation of HER3 and subsequent signaling activity, reduction of surface levels of HER3 may impede antibody targeting of tumors. 'therefore, if repeat administration of a HER3-targeting antibody is desired or required for efficacy, the administration of a HER3-targeting antibody may result in downregulation of the target and preclude re-dosing.
The present inventors have found use of antibody radioconjugates (ARCs) circumvent the problems associated with the dose-dependent downregulation of HER3 as the lower antibody doses useful in therapeutic methods may not cause HER3 downregulation. Accordingly, the present inventors have found that HER3 targeting agents including a radioisotope are effective as diagnostic and therapeutic agents for improved tumor targeting and killing of HER3-expressing cancer cells, such as certain solid tumors. In particular, therapeutic methods that may include multiple doses of a HER3-targeting agent may provide improved tumor targeting and killing without causing a detrimental level of HER3 downregulation.
[0112] Thus, according to certain aspects of the presently disclosed invention, therapeutic methods for treating HER3-positive cancers using a radiolabeled HER3 targeting agent are provided. The methods may also include diagnostic steps to determine if and/or to what extent a patient has a HER3-positive cancer and/or the localization of such cancer, for example, by identifying and/or quantifying HER3 positive cells within solid tumors or circulating in a blood sample from the patient.
[0113] According to certain aspects, the therapeutic methods include administration of a radiolabeled HER3 targeting agent, such as a radiolabeled antibody, peptide, or small molecule that targets HER3, either alone or in combination with one or more additional therapeutic agents or modalities. According to certain aspects, the additional agent or modality may be any one or more of administration of an immune checkpoint therapy, a DDRi, a CD47 blockade, a chemotherapeutic agent, a small molecule oncology drug, external beam radiation, and brachytherapy.
[0114] According to certain aspects, the radiolabeled HER3 targeting agent may be administered to the patient in a patient specific composition in one or more doses.
[0115] According to certain aspects, the patient may be monitored at intervals during the therapy for the presence of HER3-positive cells to evaluate the reduction in HER3-positive cells.
Detecting a decreased number of the HER3-positive cells after treatment with the HER3 targeting agent, as compared to the number of HER3-positive cells prior to treatment may indicate effectiveness of the I-TER3 targeting agent in treating a HER3 -p o si ti ve cancer in the mammalian subject [0116] According to certain aspects, the method of treating cancer includes identifying a patient having a HER3-positive cancer by identifying HER3-positive cells and administering to the patient an effective amount of a HER3 targeting agent, either alone or in combination with an additional method of treatment. According to certain aspects, the additional method of treatment may be any one or more of administration of an immune checkpoint therapy, a DDRi, a CD47 blockade, a chemotherapeutic agent, a small molecule oncology drug, external beam radiation and brachy. therapy.
[0117] According to certain aspects, the chemotherapeutic agent is a radiosensitizer.
[0118] According to certain aspects, the radiolabeled HER3 targeting agent can be administered to a patient that has undergone, such as recently undergone a treatment, such as surgery for treatment of the cancer, such as to remove all or a portion of a solid tumor. Thus, for example, the radiolabeled 11-ER3 targeting agent may be administered perioperatively or post-operatively.
[0119] HER3 targeting agents [0120] An object of the presently disclosed invention is to provide radiolabeled HER3-, such as human HER3-, targeting agents for diagnostic use and/or for therapeutic use, such as in the diagnosis and/or treatment of HER3-positive cancers. Radiolabeled HER3 -targeting agents can effect a therapeutic response via the delivery of DNA-damaging ionizing radiation to cells, for example, alpha-particles that induce double strand DNA breaks and cell death.
[0121] Exemplary anti-HER3 antibodies (also referred to as "HER3 antibodies"
herein) , such as anti-human HER3 antibodies, that that may be radiolabeled and embodied in and/or used in the various aspect of the presently disclosed invention include, without limitation, the following antibodies, and antibodies such as but not limited to immunoglobulins, such as but not limited to IgG, that (i) include the heavy chain variable region of the HER3 antibody or heavy chain, (ii) include 1, 2 or 3 of the heavy chain CDRs (e.g., by the Kabat definition) of the HER3 antibody or heavy chain or those recited, (iii) include the light chain variable region of the HER3 antibody or light chain, and/or (iv) include 1, 2 or 3 of the light chain CDRs (e.g., by the Kabat definition) of the HER3 antibody or light chain or those recited. It should also be understood that where a HER3 antibody heavy chain or HER3 antibody light chain is disclosed that includes an N-terminal leader sequence, also intended to be disclosed for embodiment in and use in the various aspects of the invention are corresponding heavy chains and corresponding light chains that lack the leader sequence.
[0122] An exemplary HER3 antibody that may be radiolabeled and embodied in and/or used inthe presently disclosed invention may, for example, include a murine monoclonal antibody against HER3 including a heavy chain having the amino acid sequence as set forth in SEQ ID NO.9 or 11 and/or a light chain having the amino acid sequence as set forth in SEQ ID
NO:10 or 12, or an antibody such as a humanized antibody derived from one or more of said sequences. An exemplary HER3 antibody that may be radiolabeled and embodied in and/or used in the presently disclosed invention may include or a heavy chain with an N-terminal region having the sequence set forth in SEQ ID NO:13 and/or a light chain with an N-terminal region having the sequence as set forth in SEQ ID NO:14. A HER3 antibody that may be similarly embodied or used in various aspect of the invention may, for example, include the heavy chain variable region having the amino acid sequence as set forth in SEQ ID NO:7, and/or a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:8;
and/or a heavy chain including one or more of CDR1, CDR2 and CDR3 having the amino acid sequences respectively set forth in SEQ ID NOS:1-3, and/or a light chain with one or more of the CDR1, CD2 and CDR3 having the amino acid sequences respectively set forth in SEQ ID
NOS:4-6. See FIGS. 1 and 2 for a further description of these sequences. A HER3 antibody embodied in and/or used in any of the aspects of the invention may, for example, include any combination of the aforementioned light chain sequences and/or heavy chain sequences.
[0123] An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including a CDR-H1 including SEQ ID NO:15, a CDR-H2 including SEQ ID
NO:16, and a CDR-H3 including SEQ ID NO: 17, and/or an immunoglobulin light chain variable region including a CDR-L1 including SEQ ID NO:18, a CDR-L2 including SEQ lD NO:19, and a CDR-L3 including SEQ ID NO:20. An exemplary An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including SEQ ID NO:21 and/or an immunoglobulin light chain variable region including SEQ ID NO:22. An exemplary HER3 antibody includes an immunoglobulin heavy chain amino acid sequence of SEQ ID
NO:23 and/or an immunoglobulin light chain amino acid sequence of SEQ ID NO:24.
[0124] An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including a CDR-H1 including SEQ ID NO:25, a CDR-H2 including SEQ ID
NO:26, and a CDR-H3 including SEQ ID NO:27; and/or an immunoglobulin light chain variable region including a CDR-L1 including SEQ ID NO:28, a CDR-L2 including SEQ lD NO:29, and a CDR-L3 including SEQ ID NO:30. An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including SEQ ID NO:31 and/or an immunoglobulin light chain variable region including SEQ ID NO:32.. An exemplary HER3 antibody includes an immunoglobulin heavy chain amino acid sequence of SEQ ID NO:33 and/or an immunoglobulin light chain amino acid sequence of SEQ ID NO:34 [0125] An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including a CDR-H1 including SEQ ID NO:35, a CDR-H2 including SEQ ID
NO:36, and a CDR-H3 including SEQ ID NO:37; and/or an immunoglobulin light chain variable region including a CDR-L1 including SEQ ID NO:38, a CDR-L2 including SEQ ID NO:39, and a CDR-L3 including SEQ ID NO:40. An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including SEQ ID NO:41, and/or an immunoglobulin light chain variable region SEQ ID NO:42. An exemplary HER3 antibody includes an immunoglobulin heavy chain amino acid sequence of SEQ ID NO:43 and an immunoglobulin light chain amino acid sequence of SEQ ID NO:44.
[0126] An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including a CDR-H1 including SEQ ID NO:45, a CDR-H2 including SEQ ID
NO:46, and a CDR-H3 including SEQ ID NO:47; and/or an immunoglobulin light chain variable region including a CDR-L1 including SEQ ID NO:48, a CDR-L2 including SEQ ID NO:29, and a CDR-L3 including SEQ ID NO:49. An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including SEQ ID NO:50 and/or an immunoglobulin light chain variable region including SEQ ID NO:51. An exemplary HER3 antibody includes an immunoglobulin heavy chain amino acid sequence of SEQ ID NO:52 and/or an immunoglobulin light chain amino acid sequence of SEQ ID NO:53.
[01271 An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including a CDR-H1 including SEQ ID NO:54, a CDR-H2 including SEQ ID
NO:55, and a CDR-H3 including SEQ ID NO:56; and/or an immunoglobulin light chain variable region including a CDR-L1 including SEQ ID NO:28, a CDR-L2 including SEQ ID NO:29, and a CDR-L3 including SEQ ID NO:30. An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including SEQ ID NO:57 and/or an immunoglobulin light chain variable region including SEQ ID NO:58. An exemplary HER3 antibody includes an immunoglobulin heavy chain amino acid sequence of SEQ ID NO:59 and/or an immunoglobulin light chain amino acid sequence of SEQ ID NO: 60.
[0128] An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including a CDR-H1 including SEQ ID NO:61, a CDR-H2 including SEQ ID
NO:62, and a CDR-H3 including SEQ ID NO:63; and/or an immunoglobulin light chain variable region including a CDR-L1 including SEQ ID NO:64, a CDR-L2 including SEQ ID NO:65, and a CDR-L3 including SEQ ID NO:66. An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including SEQ ID NO:67, and/or an immunoglobulin light chain variable region including SEQ ID NO:68. An exemplary HER3 antibody includes an immunoglobulin heavy chain amino acid sequence of SEQ ID NO:69 and an immunoglobulin light chain amino acid sequence of SEQ ID NO:70.
[0129] An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including a CDR-H1 including SEQ ID NO:71, a CDR-H2 including SEQ ID
NO:72, and a CDR-H3 including SEQ ID NO:66; and/or an immunoglobulin light chain variable region including a CDR-L1 including SEQ ID NO:28, a CDR-L2 including SEQ ID NO:29, and a CDR-L3 including SEQ ID NO:30. An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including SEQ ID NO:73, and/or an immunoglobulin light chain variable region including SEQ ID NO:74. An exemplary HER3 antibody includes an immunoglobulin heavy chain amino acid sequence of SEQ ID NO.75 and/or an immunoglobulin light chain amino acid sequence of SEQ ID NO:76.
[0130] An exemplary HER3 antibody includes an immunoglobulin heavy chain amino acid sequence of SEQ ID NO:77 and/or an immunoglobulin light chain amino acid sequence of SEQ ID NO.78.
[0131] An exemplary HER3 antibody includes an immunoglobulin light chain variable region including SEQ ID NOS:86, 87, 88, 89, 90 or 91 and/or a heavy chain variable region including SEQ ID NOS:79, 80, 81, 82, 83, 84 or 85.
[01321 An exemplary HER3 antibody includes an immunoglobulin heavy chain sequence including SEQ ID NO:92, 94, 95, 98 or 99 and/or an immunoglobulin light chain sequence including SEQ ID NO:93, 96, 97, 100 or 101.
[0133] Exemplary HER3 antibodies also include Barecetamab (ISU104) from Isu Abxis Co and any of the HER3 antibodies disclosed in U.S. Patent No. 10,413,607.
[01341 Exemplary HER3 antibodies also include HIMBD-001 (10D1F) from Hummingbird Bioscience Pte. and any of the HER3 antibodies disclosed in International Pub.
Nos. WO 2019185164 and W02019185878, U.S. Patent 10,662,241; and U.S. Pub.
Nos.
20190300624, 20210024651, and 20200308275.
[01351 Exemplary HER3 antibodies also include the HER2/HER3 bispecific antibody MCLA-128 (i.e., Zenocutuzumab) from Merus N.V.; and any of the HER3 antibodies, whether monospecific or multi-specific, disclosed in U.S. Pub. Nos. 20210206875, 20210155698, 20200102393, 20170058035, and 20170037145.
[0136] Exemplary HER3 antibodies also include the HER3 antibody Patritumab (U3-1287), an antibody including heavy chain sequence SEQ ID NO:106 and/or light chain sequence SEQ ID NO:7 which are reported chains of Patritumab, and any of the HER3 antibodies disclosed in U.S. Patent Nos. 9,249,230 and 7,705,130 and International Pub.
No.
W02007077028.
[01371 Exemplary HER3 antibodies also include the HER3 antibody MM-121 and any of the HER3 antibodies disclosed in U.S. Patent No. 7,846,440 and International Pub. No.
W02008100624.Exemplary HER3 antibodies also include the EGER/HER3 bispecific antibody DL1 and any of the HER3 antibodies, whether monospecific or multi-specific, disclosed in U.S.
Patent Nos. 9,327,035 and 8,597,652, U.S. Pub. No. 20140193414, and International Pub. No.
W02010108127.
[0138] Exemplary HER3 antibodies also include the HER2/HER3 bispecific antibody MM-111 and any of the HER3 antibodies, whether monospecific or multi-specific, disclosed in U.S. Pub. Nos. 20130183311 and 20090246206 and International Pub. Nos.
W02006091209 and W02005117973.
[0139] According to certain aspects, the HER3 targeting agent includes an anti-antibody that binds to an epitope of HER3 recognized by Patritumab from Daiichi Sankyo, Seribantumab (MM-121) from Merrimack Pharmaceuticals, Lumretuzumab from Roche, Elgemtumab from Novartis, GSK2849330 from GlaxoSmitliKline, CDX-3379 of Celldex Therapeutics, EV20 and MP-RM-1 from MediPharma, Barecetamab (1SU104) from lsu Abxis Co., HMBD-001 (10D1F) from Hummingbird Bioscience Pte., REGN1400 from Regeneron Pharmaceuticals, and/or AV-203 from AVEC/ Oncology. According to certain aspects, the anti-HER3 antibody is selected from one or more of Patritumab, Seribantumab or an antibody including heavy chain sequence SEQ ID NO:108 and/or light chain sequence SEQ
ID NO:109 which are reported for Seribantumab, Lumretuzumab or an antibody including heavy chain sequence SEQ ID NO:110 and/or light chain sequence SEQ ID NO:111 which are reported for Lumretuzumab, Elgemtumab or an antibody including heavy chain sequence SEQ ID
NO:112 and/or light chain sequence SEQ ID NO:113 which are reported for Elgemtumab, AV-203, CDX-3379, GSK2849330, EV20, MP-RM-1, ISU104, HMBD-001 (10D1F), and REGN1400.
Exemplary antibodies along with exemplary treatment indications are also described in Table 1.
Table 1 Company Name Product Name Targets Therapeuti Exemplary Indications (Originator) c Modality Aveo Pharmaceuticals CAN017, AV-203 HER3 Antibody Esophageal cancer, solid Inc. tumors Celldex Therapeutics CDX-3379, HER3 Antibody Head and neck cancer, solid Inc. ktn3379 tumors Daiichi Sankyo Co. patritumab HER3 Antibody Non-small cell lung cancer Ltd. (AMG 888, U3- (NSCLC), breast cancer, head 1287) and neck cancer Daiichi Sankyo Co. U3-1402 HER3 Antibody- NSCLC, breast cancer, colon Ltd. drug cancer conjugate GSK GSK2849330 HER3 Antibody Solid tumors Hummingbird HMBD-001 HER3 Antibody Gastric cancer Bioscience Pte. Ltd. (10D1F) Isu Abxis Co. Ltd. ISU104 HER3 Antibody Cancer (unspecified) MediPharma MP-R_M-1 HER3 Antibody Solid tumors MediPhanna EV20 HER3 Antibody Solid tumors Merrimack Se ribantumab HER3 Antibody NSCLC, breast cancer, Pharmaceuticals Inc. (MM-121, ovarian cancer SAR256212) Novartis AG elgem tumab HER3 Antibody Esophageal cancer, Breast (LJM716) cancer, solid tumors R_egeneron REGN1400 HER3 Antibody Cancer (unspecified) Pharmaceuticals Inc.
Roche Lumretuzumab HER3 Antibody Breast cancer, solid tumors (RG7116 or R05479599) [0140] It should be understood that wherever in this disclosure specific antibodies, specific antibody heavy chains and specific antibody light chains are disclosed, against HER3 or against any target, also intended to be disclosed for embodiment in or use in the various aspects of the invention are antibodies, such as but not limited to immunoglobulins, such as but not limited to IgG, that (i) include the heavy chain variable region of the disclosed antibody or heavy chain, (ii) include 1, 2 or 3 of the heavy chain CDRs (e.g., by Kabat definition) of the disclosed antibody or heavy chain, (iii) include the light chain variable region of the disclosed antibody or light chain, and/or (iv) include 1, 2 or 3 of the light chain CDRs (e.g., by Kabat definition) of the disclosed antibody or light chain. It should also be understood that wherever in this disclosure an antibody heavy chain or an antibody light chain is disclosed that includes an N-terminal leader sequence, also intended to be disclosed for embodiment in and use in the various aspects of the invention are corresponding heavy chains and corresponding light chains that lack the leader sequence [0141] Further, the invention provides modified versions of any of the recited amino acid sequences in which one or more isomeric amino acid replacements with exact mass, such as Leu for Ile or vice versa, are made (in, e.g., any of SEQ ID NOS:1-14 listed in FIG. 1 and 2).
Additionally, certain portions of these sequences may be substituted, such as by related portions from human immunoglobulins to form chimeric immunoglobulins (i.e., chimeric or humanized HER3). Exemplary substitutions include all or portions of the human leader sequence, and/or the conserved regions from human IgGl, IgG2, or IgG4 heavy chains and/or human Kappa light chain.
[0142] The sequence and structure of human HER3, human HER2, and human EGER
(HER1) are all known. An amino acid sequence of the human HER3 precursor protein (receptor tyrosine-protein kinase erbB-3 isoform 1 precursor NCBI Reference Sequence: NP
001973.2) is provided herein as SEQ ID NO.115. Those skilled in the art will readily appreciate that given known target protein amino acid sequences, various types of suitable antibodies and antibody mimetics specific for the extracellular domain of HER3, such as of human HER3, for use in the various aspects of the invention, may be produced using immunization and/or panning and/or antibody engineering techniques that are well established in the art.
[0143] A HER3 targeting agent that is radiolabeled for use in the various embodiments of the invention may, for example, include a HER3 binding peptide such as chelator-bearing HER3 binding peptide, such as a DOTA-bearing HER3 binding peptide, such as any of those disclosed in U.S. Pub. No. 20200121814.
[0144] According to certain aspects, the HER3 targeting agent includes/is a multi-specific targeting agent, such as a multi-specific antibody, against a first epitope of HER3 and at least a second epitope of HER3, or against HER3 and one or more different antigens such as one or more of EGFR (HERO, HER2, TROP2, and T-cell receptor gamma (TCRy) chain alternate reading frame protein (TRAP). Exemplary multi-specific antibodies that may be used include bispecific antibodies against HER3/HER2 such as MM-111 from Merrimack Pharmaceuticals or MCL A-128 (i.e., Zenocutuzumab) from Merus N.V.; or against IGF-1R/HER3 such as MM-141 (i.e., Istiratumab) from Merrimack Pharmaceuticals; or against EGFR/HER3 such as MEHD7945A (i.e., Duligotumab) from Roche or any of the cetuximab-based bispecific or multi-specific zybodies from Zyngenia Inc.
[0145] According to certain aspects, a composition including a mixture of a targeting agent, such as an antibody against HER3, and one or more antibodies against one or more different antigens, in which one or more of the antibodies is radiolabeled, is provided and/or used. An exemplary antibody composition including an antibody mixture includes at least Sym013 from Symphogen having six monoclonal antibodies against EGFR (HERO, HER2, and IIER3. In one aspect of the invention, one or more of the antibodies, such as an anti-HER3 antibody, of Sym013 may be radiolabeled. A related aspect of the invention provides a composition including targeting agents against EGFR (HER1), HER2, ad HER3, such as antibodies, in which one or more in any combination or all are radiolabeled [0146] The present invention further provides multi-specific targeting agents, compositions and related methods of treating a proliferative disease or disorder which include administration of (i) a multi-specific antibody against two or more epitopes of HER3, or against an epitope of HER3 and an epitope of one or more additional different antigens, and/or (ii) administration of a HER3 targeting agent such as an antibody and one or more discrete targeting agents directed against one or more cancer associated antigens wherein one or more of the targeting agents, such as the HER3 targeting agent is radiolabeled. The additional different antigens may, for example, be antigens whose expression is upregulated on cells involved in various diseases or disorders, such as proliferative disorders, for example, solid tumor cancers, such as those in which HER3 is also or can also be upregulated. For example, the additional different antigens may be selected from the group including mesothelin, TSHR, CD19, CD123, CD22, CD30, CD45, CD171, CD138, CS-1, CLL- 1, GD2, GD3, B-cell maturation antigen (BCMA), Tn Ag, prostate specific membrane antigen (PSMA), ROR1, FLT3, TROP2, T-cell receptor gamma (TCRy) chain alternate reading frame protein (TRAP), fibroblast activation protein (FAP), calreticulin, phosphatidylserine, GRP78 (BiP), TAG72, CD38, CD44v6, CEA, EPCAM, B7H3, KIT, IL-13Ra2, interleukin-11 receptor a (IL-11Ra), PSCA, PRS
S21, VEGFR2, LewisY, CD24, platelet-derived growth factor receptor-beta (PDGFR-beta), SSEA-4, CD20, Folate receptor alpha (FRa), ERBB2 (Her2/neu), MUC1, epidermal growth factor receptor (EGFR), EGFRvIII, NCAM, Prostase, PAP, ELF2M, Ephrin B2, IGF-I receptor, CAIX, LMP2, gp100, bcr-abl, tyrosinase, EphA2, Fucosyl GM1, sLe, GM3, DR5, 5T4, TGS5, HMWMAA, o-acetyl-GD2, Folate receptor beta, TEM1/CD248, TEM7R, CLDN6, GPRC5D, CXORF61, CD97, CD 179a, ALK, Polysialic acid, PLAC1, GloboH, UPK2, HAVCR1, ADRB3, PANX3, GPR20, LY6K, 0R51E2, TARP, WT1, NY-ES0-1, LAGE-la, MAGE-Al, legumain, HPV E6,E7, MAGE Al, MAGEA3, MAGEA3/A6, ETV6-,AML, sperm protein 17, XAGE1, Tie 2, MAD-CT-1, MAD-CT-2, Fos-related antigen 1, prostein, survivin and telomerase, PCTA-1/Galectin 8, KRAS, MelanA/MART1, Ras mutant, hTERT, sarcoma translocation breakpoints, ML-IAP, ERG (TMPRSS2 ETS fusion gene), NA17, PAX3, Androgen receptor, Cyclin B
1, MYCN, RhoC, TRP-2, CYP1B 1, BORIS, SART3, PAX5, OY- TES 1, LCK, AKAP-4, SSX2, RAGE-1, human telomerase reverse transcriptase, RU1, RU2, intestinal carboxyl esterase, mut hsp70-2, CD79a, CD79b, CD72, LAIR', FCAR, L11LRA2, CD300LF, CLEC12A, BST2, EMR2, LY75, GPC3, FCRL5, GPA7, and IGLLI.
[0003] Exemplary DRS (death receptor 5) targeting agents that may be radiolabeled, unlabeled or drug-conjugated for use in the invention include the monoclonal anti-DR5 antibodies m apatumum ab, c on atumum ab, lex atum um ab, tigatuzumab, drozitumab, and LB Y-135. Such DR5 targeting agents may, for example, be used in combination with a radiolabeled TIER3 targeting agents for the treatment of ovarian, breast, cervical prostate, gastric, bladder, lung, melanoma, colorectal and squamous cell carcinoma cancers and any of the cancers disclosed herein.
[0004] Exemplary 5T4 (Trophoblast glycoprotein (TBPG)) targeting agents that may be radiolabeled, drug-conjugated, or unlabeled for use in the invention include the anti-5T4 monoclonal antibodies MED10641, ALG.APV-527, Tb535, H6-DM5, and ZV0508, as well as Naptumomab estafenatox or the Fab portion thereof. Such 5T4 targeting agents may, for example, be used in combination with a radiolabeled HER3 targeting agent for the treatment of ovarian, head and neck, breast, prostate, gastric, bladder, lung, melanoma, colorectal and squamous cell carcinoma cancers and any of the cancers disclosed herein.
[0005] Exemplary HER2 (ERBB2) targeting agents that may be radiolabeled, drug-conjugated, or unlabeled for use in the invention include the monoclonal antibodies trastuzumab and pertuzumab. Applicants have successfully conjugated Trastuzumab with p-SCN-DOTA and radiolabeled the composition with 225Ac or 177Lu.. Exemplary ADCs targeting HER2 that may be used include fam-trastuzumab deruxtecan-nxki (Enhertug; AstraZeneca/Daiichi Sankyo) and Trastuzumab emtansine (Roche/Genentech). The anti-HER2 antibody may, for example, also be a multi-specific antibody, such as bispecific antibody, against any available epitope of 1-1ER3/1-IER2 such as MNI- 1 I 1 and MM-141/Istiratumab from Merrimack Pharmaceuticals, MCLA-128 from Merus NV, and MEEID7945A/Duligotumab from Genentech. HER2 targeting agents may, for example, be used in combination with a radiolabeled HER3 targeting agent in the treatment of HER2-expressing cancers such as ovarian, breast, metastatic breast, esophageal, lung, cervical, and endometrial cancers including but not limited to those that are both HER2-and HER3 -positive.
[0131:161 The amino acid sequences of the heavy chain and the light chain of Trastuzumab reported by DrugBank Online are: heavy chain (SEQ ID NO:102) and light chain (SEQ ID
NO:103) and a HER2 binding antibody including one or both of said chains may be embodied in or used in the various embodiments of the invention.
[0007] The amino acid sequences of the heavy chain and the light chain of Pertuzumab reported by DrugBank Online are: heavy chain (SEQ ID NO:104) and light chain (SEQ ID
NO:105) and a HER2 binding antibody including one or both of said chains may be embodied in or used in the various embodiments of the invention.
[0008] Exemplary CD33 targeting agents that may be radiolabeled, drug-conjugated, or unlabeled for use in the invention include the monoclonal antibodies lintuzumab, gemtuzumab, and vadastuximab. In combination with a radiolabeled HER3 targeting agent as disclosed herein, a CD33 targeting therapeutic agent may, for example, be used to treat solid cancers, such as ovarian, breast, cervical prostate, gastric, bladder, lung, melanoma, colorectal and squamous cell carcinoma cancers and any of the cancers disclosed herein, for example, by depleting myeloid-derived suppressor cells (MDSCs). In one aspect, the CD33 targeting agent used in combination with a radiolabeled 1-IER3 targeting agent is 225Ac-lintuzumab. In another aspect, the CD33 targeting agent used in combination with a radiolabeled HER3 targeting agent is the ADC gemtuzumab ozogamicin (MylotargR; Pfizer).
[0009] Exemplary CD38 targeting agents that may be radiolabeled, drug-conjugated, or unlabeled for use in the invention include anti-CD38 monoclonal antibodies such as daratumumab (Darzalexa); Johnson and Johnson) and isatuximab (Sarclisag;
Sanofi) or antigen-binding fragments thereof. Such CD38 targeting agents may, for example, be used in combination with the radiolabeled HER3 targeting agents in the treatment of solid tumors that may, for example, be infiltrated with CD38-positive suppressive immune cells, such as but not limited to ovarian, breast, cervical prostate, gastric, bladder, lung, melanoma, colorectal and squamous cell carcinoma cancers and any of the cancers disclosed herein.
[00101 Exemplary different antigens (over HER3) that may be targeted by a multi-specific antibody according to aspects of the present invention include at least HER1 (EGFR), HER2, and IGF-1R. Exemplary HER3 multi-specific targeting agents include multi-specific antibodies such as MM-111 from Merrimack Pharmaceuticals or MCLA-128 (i.e., Zenocutuzumab) from Merus N.V.; or against IGF-1R/HER3 such as MM-141 (i.e., Istiratumab) from Merrimack Pharmaceuticals; or against EGFR/HER3 such as MEHD7945A (i.e., Duligotumab) from Roche, the cetuximab-based bispecific zybody from Zyngenia Inc., and the multi-specific antibody composition Sym-013 from Symphogen. See also Table 2 for further description and exemplary indications.
Company Product Name Targets Therapeutic Exemplary Name Modality Indications (Originator) Merrimack Istiratumab (MM- IGF-1R;HER3 Bispecific Antibody Solid tumors Pharmaceuticals 141) Inc.
Merrimack MM-111 HER2;HER3 Bispecific Antibody Breast cancer, solid Pharmaceuticals tumors Inc.
Merus N.V. MCLA-128 HER2;HER3 Bispecific Antibody NSCLC, breast cancer, ovarian cancer, colorectal cancer, gastric cancer, endometrial cancer, solid tumors Roche Duligotuzmab EGFR;HER3 Antibody Colorectal cancer, (MEHD7945A, epithelial cancer, RG7597) head and neck cancer, solid tumors Symphogen Sym013 HER1, HER2, Antibody (mixture) Solid tumors Zyngenia Inc. Cetuximab-based EGFR;I IER3 Antibody Cancer (unspecified) bispecific zybody [01471 The present invention also provides methods of treating a proliferative disease or disorder that includes administration of a first antibody against at least one epitope of HER3, and administration of a second antibody, wherein the second antibody is against a different epitope of HER3 than the first antibody, or is against an epitope of a different antigen, such as one or more antigens selected from the list of different antigens presented above. One or more of the HER3 antibodies may be radiolabeled. Antibodies against the different antigens may, for example, also be radiolabeled in any combination.
[0148] Such combinations, presented as a multi-specific antibody or more than one monoclonal antibody as indicated above, may deliver a synergistic therapeutic effect comparable to the effectiveness of a monotherapy with only an antibody against HER3, while reducing adverse side effects of the monotherapy. Moreover, the combination may deliver an improved effectiveness over the monotherapy, which may, for example, be measured by reduction in the total tumor cell number, increase in the length of time to relapse, and other indicia of patient health.
[0149] When the methods include administration of a multi-specific antibody, the first target recognition component may, for example, include one of: a first full-length heavy chain and a first full-length light chain, a first Fab fragment, a first single-chain variable fragment (scFvs), or other type of antibody. The second target recognition component may, for example, include one of: a second full length heavy chain and a second full length light chain, a second Fab fragment, or a second single-chain variable fragment (scFvs) or other type of antibody.
Moreover, the second target recognition component may be derived from a different epitope of the HER3 antigen or may be derived from any of the antigens listed above [0150] A HER3 targeting agent may include a radioisotope, and any additional antibodies against other antigens may optionally include a radioisotope. According to certain aspects of the present invention, when the immunotherapy includes a bispecific antibody, either one or both of the first target recognition component and the second target recognition component, or any part of the hi specific targeting agent, may include a radioisotope.
[0151] According to certain aspects of the present invention, the radiolabeled targeting agent may exhibit essentially the same immunoreactivity to the antigen as a control targeting agent, wherein the control targeting agent includes the naked targeting agent or otherwise unlabeled targeting agent against the same epitope of the antigen (i.e., HER3) as the radiolabeled targeting agent.
[0152] According to certain aspects of the present invention, the targeting agent may be labeled with 225Ac, and may be at least 5-fold more effective at causing cell death of HER3-positive cells than a control monoclonal antibody, wherein the control monoclonal antibody includes a naked or unlabeled antibody against the same epitope of the antigen as the 225Ac labeled antibody. For example, a 22'Ac labeled monoclonal antibody may be at least 10-fold more effective, at least 20-fold more effective, at least 50-fold more effective, or at least 100-fold more effective at causing cell death of HER3-positive cells than the control monoclonal antibody.
[0153] According to certain aspects of the present invention, the methods may include administration of labeled and unlabeled (e.g., "naked") fractions of the HER3 targeting agent, such as an antibody, antibody fragment, etc. For example, the un-labeled fraction may include the same antibody against the same epitope as the labeled fraction. In this way, the total radioactivity of the antibody may be varied or may be held constant while the overall antibody protein concentration may be held constant or may be varied, respectively. For example, the total protein concentration of un-labeled antibody fraction administered may vary depending on the exact nature of the disease to be treated, age and weight of the patient, identity of the monoclonal antibody, and the label (e.g., radionuclide) selected for labeling of the monoclonal antibody.
[0154] According to certain aspects of the present invention, the effective amount of the anti-HER3 antibody is a maximum tolerated dose (MTD) of the anti-HER3 antibody.
[0155] According to certain method aspects of the present invention, when more than one antibody is administered, the antibodies may be administered at the same time.
As such, according to certain aspects of the present invention, the antibodies may be provided in a single composition. Alternatively, the two antibodies may be administered sequentially. As such, the radiolabeled IfER3 targeting agent may be administered before the second antibody, after the second antibody, or both before and after the second antibody. Moreover, the second antibody may be administered before the radiolabeled HER3 targeting agent, after the radiolabeled HER3 targeting agent, or both before and after the radiolabeled HER3 targeting agent.
[0156] According to certain aspects of the methods of the present invention, a radiolabeled HER3 targeting agent may be administered according to a dosing schedule selected from the group consisting of one every 7, 10, 12, 14, 20, 24, 28, 35, and 42 days throughout a treatment period, wherein the treatment period includes at least two doses.
[0157] According to certain aspects of the present invention, the radiolabeled targeting agent may be administered according to a dose schedule that includes 2 doses, such as on days 1 and 5, 6, 7, 8, 9, or 10 of a treatment period, or days 1 and 8 of a treatment period.
[0158] Administration of the radiolabeled HER3 targeting agents of the present invention, in addition to other therapeutic agents, may be provided in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated.
Administration may be intratracheal, intranasal, epidermal and transdermal, oral or parenteral.
Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration In some embodiments a slow-release preparation including the targeting agents(s) and/or other therapeutic agents may be administered. The various agents may be administered as a single treatment or in a series of treatments that continue as needed and for a duration of time that causes one or more symptoms of the cancer to be reduced or ameliorated, or that achieves another desired effect.
[0159] The dose(s) may vary, for example, depending upon the identity, size, and condition of the subject, further depending upon the route by which the composition is to be administered and the desired effect. Appropriate doses of a therapeutic agent depend upon the potency with respect to the expression or activity to be modulated. The therapeutic agents can be administered to an animal (e.g., a human) at a relatively low dose at first, with the dose subsequently increased until an appropriate response is obtained.
[0160] The radiolabeled HER3 targeting agent may be administered simultaneously or sequentially with the one or more additional therapeutic agents. Moreover, when more than one additional therapeutic agent is included, the additional therapeutic agents may be administered simultaneously or sequentially with each other and/or with the radiolabeled HER3 targeting agent.
[0161] Radiolabeling the HER3 targeting agent [0162] The HER3 targeting agent and other targeting agents disclosed herein may, for example, be labeled with a radioisotope, such as a beta emitter (e.g. 177Lu) or an alpha emitter (e.g., 225Ac), through conjugation of a chelator molecule, and chelation of the radioisotope thereto. According to certain aspects, the targeting agent may be an antibody against that is deglycosylated in the constant region, such as at asparagine-297 (Asn-297, N297; Kabat number) in the heavy chain CH2 domain, for the purpose of uncovering a unique conjugation site, glutamine (i.e., Gln-295, Q295) so that it is available for conjugation with bifunctional chelator molecules.
[0163] According to certain aspects, the radiotherapeutic may be an antibody that may have reduced disulfide bonds such as by using reducing agents, which may then be converted to dehydroalanine for the purpose of conjugating with a bifunctional chelator molecule.
[0164] According to certain aspects, the radiotherapeutic may be an antibody for which the disulfide bonds have been reduced using reducing agents, which is then conjugated via aryl bridges with a bifunctional chelator molecule. For example, according to certain aspects a linker molecule such as 3,5-bis(bromomethyl)benzene may be used to bridge the free sulfhydryl groups on the antibody.
[0165] According to certain aspects, the radiotherapeutic may be an antibody that may have certain specific existing amino acids replaced with cysteine(s) that then can be used for site-specific labeling.
Exemplary chelators that may be linked to targeting agents in the various aspects of the invention include: 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) or a derivative thereof; 1,4,7-triazacyclononane-1,4-diacetic acid (NODA) or a derivative thereof; 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) or a derivative thereof;
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or a derivative thereof; 1,4,7-triazacyclononane, 1-glutaric acid-4,7-diacetic acid (NODAGA) or a derivative thereof; 1,4,7,10-tetraazacyclodecane, 1-glutaric acid-4,7,10-triacetic acid (DOTAGA) or a derivative thereof;
1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) or a derivative thereof;
1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-di acetic acid (CB-TE2A) or a derivative thereof;
diethylene triamine pentaacetic acid (DTPA), its diester, or a derivative thereof, 2-cyclohexyl diethylene triamine pentaacetic acid (CHX-A"-DTPA) or a derivative thereoff, deforoxamine (DFO) or a derivative thereof, 1,2[[6-carboxypyridin-2-yl]methylamino]ethane (1-12dedpa) or a derivative thereof; DADA or a derivative thereof; 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic acid) (DOTP) or a derivative thereof, 4-amino-6-[[16-[(6-carboxypyridin-2-yl)methyl]-1,4,10,13-tetraoxa-7,16-diazacyclooctadec-7-ylimethylThyridine-2-carboxylic acid (VIACROPA-NI-12) or a derivative thereof; MACROPA or a derivative thereof;
1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (TCMC) or a derivative thereof, { 4- [2-(bi s-carboxymethylamino)-ethyl]-7-carb oxym ethyl-[1,4, 7]tri azonan-l-y1}-aceti c acid (NETA) or a derivative thereof, Diamsar or a derivative thereof, 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid (TRAP, PRP9, TRAP-Pr) or a derivative thereof; N,N'-bis(6-carboxy-2-pyridylmethyl)ethylenediamine-N,N'-diacetic acid (H4octapa) or a derivative thereof; N,N'41-benzy1-1,2,3-triazole-4-ylimethyl-N,N'46-(carboxy)pyridin-2-y1]-1,2-diaminoethane (H2azapa) or a derivative thereof; N,N"-[[6-(carboxy)pyridin-yl]methyl]diethylenetriamine-N,N,N"-triacetic acid (H5decapa) or a derivative thereof; N,N'-bis(2-hydroxy-5-sulfobenzyl)ethylenediamine-N,N'-diacetic acid (SHBED) or a derivative thereof; N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HEED) or a derivative thereof; 3,6,9,15-tetraazabicyclo[9.3 1]pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid (PCTA) or a derivative thereof; desferrioxamine B (DFO) or a derivative thereof; N,N'-(methylenephosphonate)-N,N'46-(methoxycarbonyl)pyridin-2-yl]methy1-1,2-diaminoethane (H6phospa) or a derivative thereof; 1,4,7,10,13,16-hexaazacyclohexadecane-N,N',N",N",N"",N'""-hexaacetic acid (HEHA) or a derivative thereof;
1,4,7,10,13-pentaazacyclopentadecane-N,N',N",N"',N""-pentaacetic acid (PEPA) or a derivative thereof; or 3,4,3-L1(1,2-HOPO) or a derivative thereof [0166] According to certain aspects, the targeting agent may be radiolabeled through chemical conjugation of suitable bifunctional chelators that can chelate one or more radionuclides. Exemplary chelator molecules that may be used include p-SCN-Bn-DOTA, NH2-DOTA, NH2-(CH2)1-20-DOTA, NH2-(PEG)3_20-DOTA, HS-DOTA, HS-(CH2)1-20-DOTA, HS-(PEG)1-20-DOTA, dibromo-S-(CH2)1-2o-DOTA, dibromo-S-(PEG)1-20-DOTA, p-SCN-Bn-DOTP, NH2-DOTP, NH2-(CH2)1-20-DOTP, NH2-(PEG)1-20-DOTP, HS-DOTP, HS-(CH2)1-20-DOTP, HS-(PEG)1_20-DOTP, dibromo-S-(CH2)3.20-DOTP, and dibromo-S-(PEG)1.20-DOTP.
[0167] The chelator molecules may, for example, be attached to a targeting agent through a linker molecule. Exemplary linker molecules include:
-CH2(C6H4)NH2 or -CH2(C6H4)NH-X-Y, wherein X is -R2-CH2CH20(CH2CH20)11CH2CH2-, -R2-CH2CH2NHC(0)CH2CH20(CH2CH20)11CH2CH2-, -R2-(CH2)nCH2-, -R2-CH2CH2NHC(0)(CH2)nCH2-, -R2-CH(C(0)R3)CH2-, wherein R3 is -OH or a short peptide (1-20 amino acids), -R2-CH2CH20(CH2CH20)CH2C(0)0-, or -R2-CH2CH2NFIC(0)CH2CH20(CH2CH20)nCH2CC(0)0-, wherein n is 1-20, and R2 is -C(0)- or -C(S)NH-; and Y is -NH2 or -SR4-, wherein R4 is -H or -CH2-3,5-bis(bromomethyl)benzene.
[0168] Targeting agents, such as protein targeting agents, for example antibodies and antigen-binding antibody fragments, and peptide targeting agents may, for example, be conjugated with a chelator for radiolabeling the targeting agent via chelation of a radionuclide.
Such protein or peptide targeting agents, for example, that include lysine(s), may conveniently be conjugated to a DOTA chelating moiety using the bifunctional agent S-2-(4-Isothiocyanatobenzy1)-1,4,7,10-tetraazacyclododecane tetraacetic acid a/k/a/
"p-SCN-Bn-DOTA" (Catalog # B205; Macrocyclics, Inc., Plano, TX, USA). p-SCN-Bn-DOTA may be synthesized by a multi-step organic synthesis fully described in U.S. Patent No. 4,923,985.
Chelation of a radionuclide by the DOTA moiety may be performed prior to chemical conjugation of the antibody with p-SCN-Bn-DOTA and/or after said conjugation.
[0169] Methods for labeling a chelator-conjugated targeting agent with an exemplary radionuclide are described in in Example 1.
[0170] Diagnostic aspects [0171] The presently disclosed methods may include diagnosing the subject to ascertain if HER3-positive cells are present, to what extent they are, and/or their localization. HER3-positive cells may be present in a number of biological specimens, such as in circulating cells in a sample of blood from the subject or tumor cells in a biopsy of the subject.
In one aspect, the diagnosing step may generally include obtaining a sample of blood or tissue from the subject and mounting the sample on a substrate. The presence or absence of the HER3 antigen may be detected using a diagnostic antibody, peptide, or small molecule, wherein the diagnostic antibody peptide, or small molecule is labeled with any of the standard imaging labels known in the art.
Exemplary labeling agents include, for example, radiolabels such as 3H, 14C, 32-, "S, and 1251;
fluorescent or chemiluminescent compounds, such as fluorescein isothiocyanate, rhodamine, or luciferin; and enzymes, such as alkaline phosphatase, 13-gal actosidase, or horseradish peroxidase.
An exemplary HER3 targeting agent used in such a diagnostic assay includes a human or humanized antibody against HER3.
[0172] In another aspect, the methods may include diagnosing the subject to ascertain if HER3-positive cells are present using a HER3 targeting agent labeled with a radionuclide such as any of "F, 11C, "Ga, "Cu, "Zr, or 1241, for PET imaging, or 99Tc or n'In, for SPECT
imaging. Accordingly, the method may include administering to the subject a HER3 targeting agent labeled with one or more of 1-8F, "Ga, 64Cu, "Zr, 1 99mTC, or Win, and performing a non-invasive imaging technique on the subject, such as performing a PET or SPECT scan on the subject. The method may include administering the radiolabeled HER3 targeting agent for imaging to the subject and, after an amount of time sufficient for the targeting agent to bind to target in the subject's tissues, performing the imaging. The amount of time sufficient for the targeting agent to bind to target in the subject's tissues may, for example, be at least 20 minutes, at least 30 minutes, at least 60 minutes, or any number or subrange of minutes in the range 20 minutes to 360 minutes. According to certain one aspect of the method, the radiolabeled HER3 targeting agent may include 68Cia, "Zr, or 1111n, and may be labeled using any of the methods disclosed herein (e.g., such as disclosed in Example 1).
[0173] If the subject has HER3-positive cancer cells, for example, beyond a predetermined or preselected threshold level, or other indications of a HER3-positive cancer/tumor, the therapeutic methods of the presently disclosed invention may be carried out, i.e., administration of a therapeutically effective amount of a radiolabeled 1-IER3 targeting agent, alone or in combination with one or more additional therapeutic agents may be performed.
[0174] Additional therapeutic agents and modalities [0175] The methods of the present invention that include administration of a radiolabeled TIER3 targeting agent therapeutic, alone or in combination with other targeting agents, may further include administration of an additional therapeutic agent or modality.
According to certain aspects, the additional agent may be relevant for the disease or condition being treated by the radiolabeled HER3 targeting agent. Such administration may be simultaneous, separate or sequential with the administration of the effective amount of the HER3 targeting agent. For simultaneous administration, the agents may be administered as one composition, or as separate compositions, as appropriate.
[0176] Exemplary additional therapeutic agents and modalities that may be used in combination or conjunction with a radiolabeled HER3 targeting agent include at least chemotherapeutic agents, small molecule oncology drugs, anti-inflammatory agents, immunosuppressive agents, immunomodulatory agents, include immune checkpoint therapies, DDR inhibitors, CD47 blockades, external beam radiation, brachytherapy, or any combination thereof. Exemplary additional agents and treatment modalities that may be used in combination or conjunction with a radiolabeled HER3 targeting agent alone or in combination other targeting agents as disclosed herein are further described below.
[0177] A. Chemotherapeutic and other small molecule agents [0178] Exemplary chemotherapeutic agents include, but are not limited to, anti-neoplastic agents including alkylating agents including: nitrogen mustards, such as mechlorethamine, cyclophosphamide, ifosfamide, melphalan and chlorambucil;
nitrosoureas, such as carmustine (BCNU), lomustine (CCNU), and semustine (methyl-CCNU);
TemodalTm (temozolomide), ethylenimines/methylmelamine such as thriethylenemelamine tri ethylene, thi ophosph orami de (thi otep a), h ex am ethyl m el amine (TIMM, tretam i n e); alkyl sulfonates such as busulfan; triazines such as dacarbazine (DUO;
antimetabolites including folic acid analogs such as m eth otrex ate and tri m etrex ate, pyri mi dine analogs such as 5-fluorouracil (5FU), fluorodeoxyuridine, gemcitabine, cytosine arabinoside (AraC, cytarabine), 5-azacytidine, 2,2'-difluorodeoxycytidine, purine analogs such as 6-mercaptopurine, 6-thioguamne, azathioprine, T-deoxycoformycin (pentostatin), erythrohydroxynonyladenine (EHNA), fludarabine phosphate, and 2-chlorodeoxyadenosine (cladribine, 2-CdA); natural products including antimitotic drugs such as paclitaxel, vinca alkaloids including vinblastine (VLB), vincristine, and vinorelbine, taxotere, estramustine, and estramustine phosphate;
pipodophylotoxins such as etoposide and teniposide; antibiotics such as actinomycin D, daunomycin (rubidomycin), doxorubicin, mitoxantrone, idarubicin, bleomycins, plicamycin (mithramycin), mitomycin C, and actinomycin; enzymes such as L-asparaginase;
biological response modifiers such as interferon-alpha, IL-2, G-CSF and GM-CSF;
miscellaneous agents including platinum coordination complexes such as oxaliplatin, cisplatin and carboplatin, anthracenediones such as mitoxantrone, substituted urea such as hydroxyurea, methylhydrazine derivatives including N-methylhydrazine (MIH) and procarbazine, adrenocortical suppressants such as mitotane (o, p-DDD) and aminoglutethimide; hormones and antagonists including adrenocorti costeroi d antagonists such as predni sone and equivalents, dex am ethason e and aminoglutethimide; GemzarTM (gemcitabine), progestin such as hydroxyprogesterone caproate, medroxyprogesterone acetate and megestrol acetate; estrogen such as diethylstilbestrol and ethinyl estradiol equivalents; antiestrogen such as tamoxifen, androgens including testosterone propionate and fluoxymesterone/equivalents; anti androgens such as flutami de, gonadotropin-releasing hormone analogs and leuprolide; and non-steroidal antiandrogens such as flutamide.
[0179] Therapies targeting epigenetic mechanisms including, but not limited to: (i) histone deacetylase (HDAC) inhibitors such as Vorinostat (suberoylanilide hydroxamic acid;
SAHA), Romidepsin, Belinostat (PDX101), Panobinostat (LBH589) and Tucidinostat, demethylating agents (e.g., Vidaza); (ii) LSD1 inhibitors such as seclidemstat, TCP
(tranylcypromine), ORY-1001 (iadademstat), GSK2879552 (GSK), INCB059872 (Imago BioSciences), IMG-7289 (Bomedemstat; Imago BioSciences), ORY-2001 (Vafidemstat), and CC-90011 (Celgene); and (iii) release of transcriptional repression (ATRA) therapies, may also be used in combination or conjunction with a radiolabeled HER3 targeting agent and/or other radiolabeled targeting agents and combinations thereof as disclosed herein.
[0180] According to certain aspects of the present invention, the chemotherapeutic agents include at least radiosensitizers, such as temozolomide, cisplatin, and/or fluorouracil.
[0181] The additional agents may, for example, include a bc1-2 inhibitor such as navitoclax or venetoclax (Venelexta ; Abbvie) and the combination may, for example, be used for the treatment of solid tumors such as breast cancers and lunger cancer such as small cell lung carcinoma (SCLC).
[0182] The additional agents may, for example, include a cyclin-dependent kinase CDK4 and CDK6 inhibitor such as palbociclib (Ibrancee; Pfizer) and the combination may, for example, be used for the treatment of solid cancers such as breast cancers such as HR-positive and HER2-negative breast cancer, with or without an aromatase inhibitor.
[01831 The additional agents may, for example, include erlotinib (Tarceva0;
Roche) and the combination may, for example, be used for the treatment of solid tumor cancers such as non-small cell lung cancer (NSCLC), for example, with mutations in the epidermal growth factor receptor (EGFR) and pancreatic cancer.
[0184] The additional agents may, for example, include sirolimus or everolimus (Affinitore; Novartis) and the combination may, for example, be used for the treatment of solid tumor cancers such as melanoma and breast cancer.
[0185] The additional agents may, for example, include pemetrexed (Alimtag;
Eli Lilly) and the combination may, for example, be used for the treatment of solid cancers such as mesothelioma such as pleural mesothelioma and lung cancer such as non-small cell lung cancer (NSCLC).
[01861 The additional therapeutic agents may, for example, be administered according to any standard dose regime known in the field. For example, therapeutic agents may be administered at concentrations in the range of 1 to 500 mg/m2, the amounts being calculated as a function of patient surface area (m2). For example, exemplary doses of the chemotherapeutic paclitaxel may include 15 mg/m2 to 275 mg/m2, exemplary doses of docetaxel may include 60 mg/m2 to 100 mg/m2, exemplary doses of epithilone may include 10 mg/m2 to 20 mg/m2, and an exemplary dose of calicheamicin may include 1 mg/m2 to 10 mg/m2. While exemplary doses are listed herein, such are only provided for reference and are not intended to limit the dose ranges of the drug agents of the presently disclosed invention.
[01871 R. External Ream Radiation and/or Braelatherapv [0188] The additional therapeutic modality administered in conjunction with the HER3 targeting agent, and optionally any other of the additional therapeutics disclosed herein, may be an ionizing radiation, such as administered via external beam radiation or brachytherapy. Such radiation generally refers to the use of X-rays, gamma rays, or charged particles (e.g., protons or electrons) to generate ionizing radiation, such as delivered by a machine placed outside the patient's body (external-beam radiation therapy) or by a source placed inside a patient's body (internal radiation therapy or brachytherapy).
[0189] The external beam radiation or brachytherapy may enhance the targeted radiation damage delivered by the radiolabeled 1-IER3 targeting agent and may thus be delivered sequentially with the HER3 targeting agent, such as before and/or after the HER3 targeting agent, or simultaneous with the HER3 targeting agents.
[0190] The external beam radiation or brachytherapy may be planned and administered in conjunction with imaging-based techniques such as computed tomography (CT) and/or magnetic resonance imaging (MRI) to accurately determine the dose and location of radiation to be administered. For example, a patient treated with any of the radiolabeled HER3 targeting agents disclosed herein may be imaged using either of CT or MRI to determine the dose and location of radiation to be administered by the external beam radiation or brachytherapy.
[0191] In various embodiments, the radiation therapy may be selected from the group consisting of total all-body radiation therapy, conventional external beam radiation therapy, stereotactic radiosurgery, stereotactic body radiation therapy, 3-D conformal radiation therapy, intensity-modulated radiation therapy, image-guided radiation therapy, tomotherapy, and brachytherapy. According to certain aspects, the radiation therapy may be provided as a single dose or as fractionated doses, e.g., as 2 or more fractions. For example, the dose may be administered such that each fraction includes 2-20 Gy (e.g., a radiation dose of 50 Gy may be split up into 10 fractions, each including 5 Gy). The 2 or more fractions may be administered on consecutive or sequential days, such as once in 2 days, once in 3 days, once in 4 days, once in 5 days, once in 6 days, once in 7 days, or in a combination thereof.
[0192] C. Immune Checkpoint Therapies [0193] The additional agent(s) administered in conjunction with the HER3 targeting agent may be an immune checkpoint therapy. Cancer cells have developed means to evade the standard checkpoints of the immune system. For example, cancer cells have been found to evade immunosurveillance through reduced expression of tumor antigens, downregulation of 1VIEIC
class I and II molecules leading to reduced tumor antigen presentation, secretion of immunosuppressive cytokines such as TGFb, recruitment or induction of immunosuppressive cells such as regulatory T cells (Treg) or myeloid-derived suppressor cells (MDSC), and overexpression of certain ligands [e.g., programmed death ligand-1 (PD-L1)]
that inhibit the host's existing antitumor immunity.
[0194] Another major mechanism of immune suppression by cancer cells is a process known as "T-cell exhaustion", which results from chronic exposure to tumor antigens, and is characterized by the upregulation of inhibitory receptors. These inhibitory receptors serve as immune checkpoints in order to prevent uncontrolled immune reactions.
[0195] Various immune checkpoints acting at different levels of T cell immunity have been described in the literature, including PD-1 (i.e., programmed cell death protein 1) and its ligands PD-Li and PD-L2, CTLA-4 (i.e., cytotoxic T-lymphocyte associated protein-4) and its ligands CD80 and CD86, LAG3 (i.e., Lymphocyte-activation gene 3), B and T
lymphocyte attenuator, TIGIT (T-cell immunoreceptor with Ig and ITIM domains), TIM-3 (i.e., T-cell immunoglobulin and mucin-domain containing protein 3), and VISTA (V-domain immunoglobulin suppressor of T cell activation).
[0196] Enhancing the efficacy of the immune system by therapeutic intervention is a particularly exciting development in cancer treatment. As indicated, checkpoint inhibitors such as CTLA-4 and PD-1 prevent autoimmunity and generally protect tissues from immune collateral damage. In addition, stimulatory checkpoints, such as 0X40 (i.e., tumor necrosis factor receptor superfamily, member 4; TNFR-SF4), CD137 (i.e., TNFR-SF9), GITR (i.e., Glucocorticoid-Induced TNFR), CD27 (i.e., TNFR-SF7), CD40 (i.e., cluster of differentiation 40), and CD28, activate and/or promote the expansion of T-cells. Regulation of the immune system by inhibition or overexpression of these proteins is an area of promising current research.
[01971 Thus, a promising therapeutic strategy is the use of immune checkpoint therapies that may remove certain blockades on the immune system that are utilized by cancer cells, in combination with the HER3 targeting agents disclosed herein. For example, antibodies against certain immune checkpoint inhibitors (ICI) may block interaction between checkpoint inhibitor proteins and their ligands, therefore preventing the signaling events that would otherwise have led to inhibition of an immune response against the tumor cell.
[0198] Moreover, there is a growing body of preclinical evidence supporting the ability of radiation to synergize with ICI antibodies, and this is also being explored in the clinic with increasing numbers of clinical trials evaluating the combination of external beam radiation with immune checkpoint therapies across various tumor types and ICI antibodies (Lamichhane, 2018).
Clinical evidence supporting this combination has been generated in melanoma, with two studies demonstrating a clinical benefit using radiation in combination with the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) ICI antibody, Ipilimumab (Tvvyman-Saint Vistor, 2015).
[0199] Accordingly, an object of the presently disclosed invention is to provide therapies for the treatment of cancer using a HER3 targeting agent in combination with one or more immune checkpoint therapies, such as an ICI antibody.
[0200] Immune checkpoint therapies of the present invention include molecules that totally or partially reduce, inhibit, interfere with or modulate one or more checkpoint proteins.
Checkpoint proteins regulate T-cell activation or function. Immune checkpoint therapies may unblock an existing immune response inhibition by binding to or otherwise disabling checkpoint inhibition. The immune checkpoint therapies may include monoclonal antibodies, humanized antibodies, fully human antibodies, antibody fragments. small molecule therapeutics, or a combination thereof.
[0201] Exemplary immune checkpoint therapies may specifically bind to and inhibit a checkpoint protein, such as the inhibitory receptors CTLA-4, PD-1, TIM-3, VISTA, BTLA, LAG-3 and TIGIT, and/or the activating receptors CD28, 0X40, CD40, GITR, CD137, CD27, and HVEM. Additionally, the immune checkpoint therapy may bind to a ligand of any of the aforementioned checkpoint proteins, such as PD-L1, PD-L2, PD-L3, and PD-L4 (ligands for PD-1); CD80 and CD86 (ligands for CTLA-4); CD137-L (ligand of CD137); and GITR-L
(ligand of GITR). Other exemplary immune checkpoint therapies may bind to checkpoint proteins such as CD226, B7-H3, B7-H4, BTLA, TIGIT, GALS, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, 76, and memory CD 8-I- (a3) T cells), CD160 (also referred to as BY55), and CGEN-15049 102021 Central to the immune checkpoint process are the CD137, C1LA-4 and PD-1 immune checkpoint pathways.
[0203] The CTLA-4 and PD-1 pathways are thought to operate at different stages of an immune response. CTLA-4 is considered the "leader" of the immune checkpoint inhibitors (ICI), as it stops potentially autoreactive T cells at the initial stage of naive T-cell activation, typically in lymph nodes. The PD-1 pathway regulates previously activated T cells at the later stages of an immune response, primarily in peripheral tissues. Moreover, progressing cancer patients have been shown to lack upregulation of PD-Li by either tumor cells or tumor-infiltrating immune cells. Immune checkpoint therapies targeting the PD-1 pathway might thus be especially effective in tumors where this immune suppressive axis is operational and reversing the balance towards an immune protective environment would rekindle and strengthen a pre-existing anti-tumor immune response. PD-1 blockade can be accomplished by a variety of mechanisms including antibodies that bind PD-1 or its ligand, PD-Li.
[0204] According to certain aspects of the presently disclosed invention, the immune checkpoint therapy may include an inhibitor of the PD-1 checkpoint, which may decrease, block, inhibit, abrogate, or interfere with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-Li and PD-L2. The inhibitor of the PD-1 checkpoint may be an anti-PD-1 antibody, antigen binding fragment, fusion proteins, oligopeptides, and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-Li and/or PD-L2.
In some embodiments, a PD-1 checkpoint inhibitor reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some embodiments, the PD-1 checkpoint therapy is an anti-PD-1 antibody.
[0205] Thus, according to certain aspects of the present invention, the immune checkpoint therapy may include a monoclonal antibody against an immune checkpoint inhibitor (ICI) such as against CTLA-4, PD-1, or PD-Li.
[0206] According to certain aspects, the ICI antibody may be an antibody against PD-1.
The ICI antibody may be an anti-PD-1 antibody, such as nivolumab. For example, the inhibitors of PD-1 biological activity (or its ligands) disclosed in U.S. Pat. No.
7,029,674. Exemplary antibodies against PD-1 include: Anti-mouse PD-1 antibody Clone J43 (Cat #BE0033-2) from BioXcell; Anti-mouse PD-1 antibody Clone RN1P1-14 (Cat #BE0146) from BioXcell;
mouse anti-PD-1 antibody Clone EH12; Merck's MK-3475 anti-mouse PD-1 antibody (Keytruda , pembrolizumab, lambrolizumab); and AnaptysBio's anti-PD-1 antibody, known as ANB011;
antibody MDX-1 106 (ONO-4538); Bristol-Myers Squibb's human IgG4 monoclonal antibody nivolumab (Opdivog, BMS-936558, MDX1106); AstraZeneca's A1\4P-514, and AMP-224; and Pidilizumab (CT-011), CureTech Ltd.
[0207] According to certain aspects, the immune checkpoint therapy is an inhibitor of PD-Li. Exemplary inhibitors of PD-Li include antibodies (e.g., an anti-PD-Li antibody, i.e., ICI
antibody), RNAi molecules (e.g., anti-PD-Li RNAi), antisense molecules (e.g., an anti-PD-Li antisense RNA), dominant negative proteins (e.g., a dominant negative PD-Li protein), and small molecule inhibitors. An exemplary anti-PD-Li antibody includes clone EH12. Exemplary antibodies against PD-Li include: Genentech's MPDL3280A (RG7446); anti-mouse PD-Li antibody Clone 10F 9G2 (Cat #BE0101) from BioXcell; anti-PD-Li monoclonal antibody MDX-1105 (BMS-936559) and BMS-935559 from Bristol-Meyer's Squibb; MSB0010718C;
mouse anti-PD-Li Clone 29E.2A3; and AstraZeneca's MEDI4736 (Durvalumab).
[0208] According to certain aspects, the immune checkpoint therapy is an inhibitor of PD-L2 or may reduce the interaction between PD-1 and PD-L2 Exemplary inhibitors of PD-L2 include antibodies (e.g., an anti-PD-L2 antibody, i.e., ICI antibody), RNAi molecules (e.g., an anti-PD-L2 RNAi), antisense molecules (e.g., an anti-PD-L2 antisense RNA), dominant negative proteins (e.g., a dominant negative PD-L2 protein), and small molecule inhibitors. Antibodies include monoclonal antibodies, humanized antibodies, deimmunized antibodies, and Ig fusion proteins.
[0209] According to certain aspects, the immune checkpoint therapy may be an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody, i.e., ICI antibody. According to one aspect, the ICI antibody may be ipilimumab. The anti-CTLA-4 antibody may block the binding of CTLA-4 to CD80 (B7-1) and/or CD86 (B7-2) expressed on antigen presenting cells.
Exemplary antibodies against CTLA-4 include: Bristol Meyers Squibb's anti-CTLA -4 antibody ipilimumab (also known as Yervoyg, MDX-010, BMS-734016 and MDX-101); anti-CTLA4 Antibody, clone 9H10 from Millipore; Pfizer's tremelimumab (CP-675,206, ticilimumab);
and anti-CTLA-4 antibody clone BNI3 from Abcam. According to certain aspects, the immune checkpoint inhibitor may be a nucleic acid inhibitor of C1LA-4 expression.
[0210] CD137 (also known "TNF receptor superfamily member 9") is a costimulatory receptor member of the tumor necrosis factor receptor superfamily, mediating CD28-dependent and independent T-cell co-stimulation (Bartkowiak, 2015). CD137 is inducibly expressed by T
cells, natural killer (NK) cells, dendritic cells (DC), B cells, and other cells of the immune system. The protein is composed of a 255-amino acid protein having a short N-terminal cytoplasmic portion, a transmembrane region, and an extracellular domain that possesses 3 cysteine-rich motifs. Ligation of CD137 by its ligand CD137L (4-1BBL; TNF
SF9), which is mainly, though not exclusively, expressed on Antigen-Presenting Cells (APCs), evokes various T
cell responses such as cell expansion, increased cytokine secretion and the prevention of activation-induced cell death. Thus, such ligation serves to activate the immune system.
However, cis-interactions between CD137 and CD137L also potently downregulate the expression of' CD137L (Kwon, 2015). The CD137 ligand thus functions to control the extent and kinetics of CD137-mediated immune system activation (Kwon, 2015).
Significantly, CD137 expressed on human NK cells becomes upregulated upon binding to anti-tumor antibodies that have become bound to tumor cells (Wei, 2014).
[0211] Thus, according to certain aspects of the presently disclosed invention, the immune checkpoint therapy may include an antibody against CD137, which could be used to activate the immune system and thereby provide a therapy for cancer in combination with the presently disclosed HER3 targeting agents. Exemplary anti-CD137 antibodies that may be used are disclosed in U.S. Publication Nos. 20140274909; 20130280265; 20130273078;
20130071403; 20120058047, 20110104049; 20110097313; 20080166336; 20080019905;
20060188439; 20060182744; 20060121030; and 20030223989.
[0212] According to certain aspects of the present invention, the immune checkpoint therapy may include more than one modulator of an immune checkpoint protein.
As such, the immune checkpoint therapy may include a first antibody or inhibitor against a first immune checkpoint protein and a second antibody or inhibitor against a second immune checkpoint protein.
[0213] D. DNA Damnee Response inhibitors [0214] The additional agents administered in conjunction with the HER3 targeting agent may be one or more DNA damage response inhibitors (DDRi). DNA damage can be due to endogenous factors, such as spontaneous or enzymatic reactions, chemical reactions, or errors in replication, or may be due to exogenous factors, such as UV or ionizing radiation or genotoxic chemicals. The repair pathways that overcome this damage are collectively referred to as the DNA damage response or DDR. This signaling network acts to detect and orchestrate a cell's response to certain forms of DNA damage, most notably double strand breaks and replication stress. Following treatment with many types of DNA damaging drugs and ionizing radiation, cells are reliant on the DDR for survival. It has been shown that disruption of the DDR can increase cancer cell sensitivity to these DNA damaging agents and thus may improve patient responses to such therapies.
[0215] Within the DDR, there are several DNA repair mechanisms, including base excision repair, nucleotide excision repair, mismatch repair, homologous recombinant repair, and non-homologous end joining. Approximately 450 human DDR genes code for proteins with roles in physiological processes. Dysregulation of DDR leads to a variety of disorders, including genetic, neurodegenerative, immune, cardiovascular, and metabolic diseases or disorders and cancers. For example, the genes OGG1 and XRCC1 are part of the base excision repair mechanism of DDR, and mutations in these genes are found in renal, breast, and lung cancers, while the genes BRCA1 and BRCA2 are involved in homologous recombination repair mechanisms and mutations in these genes leads to an increased risk of breast, ovarian, prostate, pancreatic, as well as gastrointestinal and hematological cancers, and melanoma. Exemplary DDR genes are provided in Table 3.
[02161 An object of the presently disclosed invention is to administer radiolabeled FIER3 targeting agents that deliver ionizing radiation in combination with a DDRi.
Thus, according to certain aspects, the additional agent(s) administered with the HER3 targeting agent may target proteins in the DDR, i.e., DDR inhibitors or DDRi, thus maximizing DNA damage or inhibiting the repair if the damage, such as in G1 and S-phase and/or preventing repair in G2, ensuring the maximum amount of DNA damage is taken into mitosis, leading to cell death.
DNA repair Gene Cancer mechanism examples Base Excision OGG/ Renal, breast and lung cancer Repair XRCC 1 Non-small cell lung cancer ERCC I Lung and skin cancer, and glioma Nucleotide Xeroderma pigmentosum predisposing to skin cancer.
Excision Repair XP
Also increased risk of bladder and lung cancer Lynch syndrome predisposing to colorectal cancer as well MSH2, as endometrial, ovarian, stomach, small intestine, Mismatch Repair MLHJ hepatobiliary tract, upper urinary tract, brain and skin cancer Homologous BRCA I Increased risk of breast, ovarian, prostate, pancreatic, as , Recombinant BRCA 2 well as gastrointestinal and hematological cancer, and Repair melanoma Non-homologous KU70 Breast, colorectal and lung cancer End Joining KUSO Lung cancer Cell cycle AIM Ataxia-telangiectasia predisposing to leukemia, breast and pancreatic cancer checkpoints AIR Leukemia, lymphoma, gastric and endometrial cancer [0217] Moreover, one or more DDR pathways may be targeted to ensure cell death, i.e., lethality to the targeted cancer cells. For example, mutations in the BRCA1 and 2 genes alone may not be sufficient to ensure cell death, as other pathways, such as the PARP1 base excision pathway, may act to repair the DNA damage. Thus, combinations of multiple DDRi inhibitors or combining DDRi with antiangiogenic agents or immune checkpoint inhibitors, such as listed hereinabove, are possible and an object of the presently disclosed invention.
[02181 Exemplary DDRi ¨ATM and ATR inhibitors [0219] Ataxia telangiectasia mutated (ATM) and Ataxia talangiectasia mutated and Rad-3 related (ATR) are members of the phosphatidylinositol 3-kinase-related kinase (PIKK) family of serine/threonine protein kinases.
[02201 ATM is a serine/threonine protein kinase that is recmited and activated by DNA
double-strand breaks. The ATM phosphorylates several key proteins that initiate activation of a DNA damage checkpoint, leading to cell cycle arrest, DNA repair, or cellular apoptosis. Several of these targets, including p53, CHK2, and H2AX, are tumor suppressors. The protein is named for the disorder ataxia telangiectasia caused by mutations of the ATM. The ATM
belongs to the superfamily of phosphatidylinositol 3-kinase-related kinases (PIKKs), which includes six serine/threonine protein kinases that show a sequence similarity to a phosphatidylinositol 3-kinase (PI3K).
[02211 Like ATM, ATR is one of the central kinases involved in the DDR. ATR is activated by single stranded DNA structures, which may for example arise at resected DNA
DSBs or stalled replication forks. When DNA polymerases stall during DNA
replication, the replicative helicases continue to unwind the DNA ahead of the replication fork, leading to the generation of long stretches of single stranded DNA (ssDNA).
[0222] ATM has been found to assist cancer cells by providing resistance against chemotherapeutic agents and thus favors tumor growth and survival. Inhibition of ATM and/or ATR may markedly increase cancer cell sensitivity to DNA damaging agents, such as the ionizing radiation provided by the radiolabeled HER3 targeting agent.
Accordingly, an object of the presently disclosed invention includes administration of an inhibitor of ATM (ATMi) and/or ATR (ATRi), in combination with the HER3 targeting agents, to inhibit or kill cancer cells, such as those expressing tor overexpressing HER3.
[0223] The inhibitor of ATM (ATMi) or ATR (ATRi) may be an antibody, peptide, or small molecule that targets ATM or ATR, respectively. Alternatively, an ATMi or ATRi may reduce or eliminate activation of ATM or ATR by one or more signaling molecules, proteins, or other compounds, or can result in the reduction or elimination of ATM or ATR
activation by all signaling molecules, proteins, or other compounds. ATMi and/or ATRi also include compounds that inhibit their expression (e.g., compounds that inhibit ATM or ATR
transcription or translation). An exemplary ATMi KU-55933 suppresses cell proliferation and induces apoptosis.
Other exemplary ATMi include at least KU-59403, wortmannin, CP466722, and KU-60019.
Exemplary ATRi include at least Schisandrin B, NU6027, NVP-BEA235, VE-821, VE-822, AZ20, and AZD6738.
[0224] Exemplary DDRi ¨ Weel inhibitors [02251 The checkpoint kinase Weel catalyzes an inhibitory phosphorylation of both CDK1 (CDC2) and CDK2 on tyrosine 15, thus arresting the cell cycle in response to extrinsically induced DNA damage. Deregulated Weel expression or activity is believed to be a hallmark of pathology in several types of cancer. For example, Weel is often overexpressed in glioblastomas, malignant melanoma, hepatocellular carcinoma, breast cancer, colon carcinoma, lung carcinoma, and head and neck squamous cell carcinoma. Advanced tumors with an increased level of genomic instability may require functional checkpoints to allow for repair of such lethal DNA damage. As such, the present inventors believe that Weel represents an attractive target in advanced tumors where its inhibition is believed to result in irreparable DNA
damage. Accordingly, an object of the presently disclosed invention includes administration of an inhibitor of Weel, in combination with the 1-IER3 targeting agents, to inhibit or kill cancer cells, such as those expressing tor overexpressing HER3.
[0226] A Weel inhibitor may be an antibody, peptide, or small molecule that targets Weel. Alternatively, a Weel inhibitor may reduce or eliminate Weel activation by one or more signaling molecules, proteins, or other compounds, or can result in the reduction or elimination of Weel activation by all signaling molecules, proteins, or other compounds.
The term also includes compounds that decrease or eliminate the activation or deactivation of one or more proteins or cell signaling components by Weel (e.g., a Weel inhibitor can decrease or eliminate Weel-dependent inactivation of cyclin and Cdk activity). Weel inhibitors also include compounds that inhibit Weel expression (e.g., compounds that inhibit Weel transcription or translation).
[0227] Exemplary Weel inhibitors include AZD-1775 (i.e., adavosertib), and inhibitors such as those described in, e.g., U.S. Patent Nos, 7,834,019; 7,935,708;
8,288,396; 8,436,004;
8,710,065; 8,716,297; 8,791,125; 8,796,289; 9,051,327; 9,181,239; 9,714,244;
9,718,821; and 9,850,247; U.S. Pub. Nos. US 20100113445 and 20160222459; and International Pub. Nos.
W02002090360, 2015019037, 2017013436, 2017216559, 2018011569, and 2018011570.
[0228] Further Weel inhibitors include a pyrazolopyrim i din e derivative, a pyridopyrimidine, 4-(2-chloropheny1)-9-hydroxypyrrolo[3,4-c]carbazole-1,3-(2H, 6H)-dione (CAS No. 622855-37-2), 6-buty1-4-(2-chloropheny1)-9-hydroxypyrrolo[3,4-c]carbazole-1,3-(2H,6H)-dione (CAS No. 62285550-9), 4-(2-pheny1)-9-hydroxypyrrolo[3,4-c]carbazole-1,3-(2H,6H)-dione (CAS No. 1177150-89-8), and an anti-Weel small interfering RNA
(siRNA) molecule.
[0229] Exemplary DDRi - PARP inhibitors [0230] Another exemplary type of DDRi that may be used are inhibitors of poly(ADP-ribose) polymerase ("PARP"). Inhibitors of the DNA repair protein PARP, referred to individually and collectively as "PARPi", have been approved for use in a range of solid tumors, such as breast and ovarian cancer, particularly in patients having BRCA1/2 mutations. BRCA1 and 2 function in homologous recombination repair (HRR). When mutated, they induce genomic instability by shifting the DNA repair process from conservative and precise HRR to non-fidelitous methods such as DNA endjoining, which can produce mutations via deletions and insertions.
[0231] PARPi have been shown to exhibit synthetic lethality, as exhibited by potent single agent activity, in BRCA1/2 mutant cells. This essentially blocks repair of single-strand DNA breaks. Since 1-112,1t is not functional in these tumor cells, cell death results. Because most tumors do not carry BRCA1 or BRCA2 mutations, the potency of PARPi in such tumors is far less pronounced.
[0232] To date, the FDA has approved four PARPi drugs (olaparib, niraparib, rucaparib and talazoparib) as monotherapy agents, specifically in patients with germline and somatic mutations in the BRCA1 and BRCA2 genes. Along with veliparib, olaparib, niraparib and rucaparib were among the first generation of PARPi that entered clinical trials. Their IC50 values were found to be in the nanomolar range. In contrast, second generation PARPi like talazoparib have IC50 values in the picomolar range.
[0233] These PARPi all bind to the binding site of the cofactor, b nicotinamide adenine dinucleotide (b-NAD+), in the catalytic domain of PARP1 and PARP2. The PARP
family of enzymes use NAD+ to covalently add Poly(ADP-ribose) (PAR) chains onto target proteins, a process teitned "PARylation.- PARP1 (which is the best-studied member) and PARP2, are important components of the DNA damage response (DDR) pathway, PARP1 is involved in the repair of single-stranded DNA breaks, and possibly other DNA lesions (Woodhouse, et al.;
Krishnakumar, et al.). Through its zinc finger domains, PARP1 binds to damaged DNA and then PARylates a series of DNA repair effector proteins, releasing nicotinamide as a by-product (Krishnakumar, et al.). Subsequently, PARP I auto-PARylation leads to release of the protein from the DNA. The available PARPi, however, differ in their capability to trap PARP1 on DNA, which seems to correlate with cytotoxicity and drug efficacy. Specifically, drugs like talazoparib and olaparib are more effective in trapping PARP1 than are veliparib (Murai, et al., 2012; Murai, et al., 2014).
[0234] The efficacy of PARPi in ovarian cancer and breast cancer patients who have loss-of-function mutations in BRCA1 or BRCA2 genes is largely attributed to the genetic concept of synthetic lethality. that proteins of BRCA 1 and 2 normally maintain the integrity of the genome by mediating a DNA repair process, known as homologous recombination repair (HRR); and PARPi causes a persistent DNA lesion that, normally, would otherwise be repaired by HR. In the presence of PARPi, PARP1 is trapped on DNA which stalls progression of the replication fork. this stalling is cytotoxic unless timely repaired by the filt system. In cells lacking effective HR, they are unable to effectively repair these DNA lesions, and thus die.
[0235] Again, mutations in BRCA genes and others in the 1-1R,R system are not prevalent in many cancer types. So, to better harness the therapeutic benefits of PARPi in such cancers, one can induce "artificial- synthetic lethality by pairing a PARPi with either chemotherapy or radiation therapy. Preclinical studies have demonstrated that combining radiation therapy and PARPi can increase the sensitivity of BRCA1/2 mutant tumor cells to PARP
inhibition and extend the sensitivity of non-mutant BRCA tumors to PARP inhibition.
Additional studies have shown that ionizing radiation (lift) itself can mediate PARPi synthetic lethality in tumor cells.
[0236] Accordingly, an object of the presently disclosed invention is to administer radiolabeled HER3 targeting agents that deliver ionizing radiation in combination with a PARPi.
[0237] In the various embodiments of this invention, the PARPi may be any known agent performing that function, and preferably, one approved by the FDA. Preferably, the PARPi is olaparib (Lynparza0), niraparib (Zejula8), rucaparib (Rubracag) or talazoparib (Talzenna8).
[0238] Clinically, therapy with PARPi has resulted in sustained anti-tumor responses in a range of cancers including ovarian, prostate, pancreatic, and triple-negative breast cancers (TNBC). In one clinical trial, TNBC patients with germline BRCA1/2 mutations were treated with the PARPi, olaparib. While this therapy demonstrated a higher disease stabilization rate in BRCA1/2-mutant compared to non-mutant patients, there were no sustained responses achieved in either cohort (Gelmon, 2011).
[0239] The present inventors realized that the effect of PARPi may be improved through increases in dsDNA breaks induced by ionizing radiation provided by a RER3 targeting agent while these repair pathways are being blocked by the PARPi. Exemplary PARPi include olaparib, niraparib, rucaparib and talazoparib.
[0240] E. CD47 blockades [0241] The additional agents administered with the HER3 targeting agent may be a CD47 blockade, such as any agent that interferes with, or reduces the activity and/or signaling between CD47 (e.g., on a target cell) and SIRPa (e.g., on a phagocytic cell) through interaction with either CD47 or SIRPa. Non-limiting examples of suitable CD47 blockades include CD47 and/or STRPa reagents, including without limitation SIRPa polypepti des, anti-STRPa antibodies, soluble CD47 polypeptides, and anti-C1147 antibodies or antibody fragments.
[0242] Additional examples of a CD47 blockade include agents that modulate the expression of CD47 and/or SIRPa. For example, such agents may include nucleic acid approaches such as phosphorodiamidate morpholino oligomers (PMO) that block translation of CD47 or antibodies specific for human CD47 that modulate, e.g., block, inhibit, reduce, antagonize, neutralize or otherwise interfere with CD47 expression. The CD47 antibodies or anti-sense approaches may inhibit CD47 expression (e.g., inhibiting cell surface expression of CD47), activity, and/or signaling, or may interfere with the interaction between CD47 and SIRPa. The agents provided herein completely or partially reduce or otherwise modulate CD47 expression or activity upon binding to, or otherwise interacting with, CD47, e.g., a human CD47.
The reduction or modulation of a biological function of CD47 is complete, significant, or partial upon interaction between the antibodies and the human CD47 polypeptide and/or peptide. The agents are considered to inhibit CD47 expression or activity when the level of CD47 expression or activity in the presence of the antibody is decreased by at least 50%, e.g., by 60%, 70%, 80%, 90%, 95%, 96%, 98%, 99%, or 100% as compared to the level of CD47 expression or activity in the absence of interaction, e.g., binding, with the antibody described herein.
[0243] According to certain aspects, an anti-CD47 agent is an antibody that specifically binds CD47 (i.e., an anti-CD47 antibody) and reduces the interaction between CD47 on one cell (e.g., an infected cell) and S1RPa, on another cell (e.g., a phagocytic cell).
Non-limiting examples of suitable antibodies include clones B6H12, 5F9, 8B6, and C3 and any of those described in International Pub. No. W02011/143624 and U.S. Pub 20210246206. Suitable anti-antibodies include fully human, humanized or chimeric versions of such antibodies.
[0244] Exemplary human or humanized antibodies especially useful for in vivo applications in humans due to their low antigenicity include at least monoclonal antibodies against CD47, such as Hu5F9-G4, a humanized monoclonal antibody available from Gilead as Magrolimab (Sikic, et al. (2019) Journal of Clinical Oncology 37:946);
Lemzoparlimab and TJC4 from I-Mab Biopharma; A0-176 from Arch Oncology, Inc; AK117 from Akesobio Australia Pty; IMC-002 from Innovent Biologics; ZL-1201 from Zia Lab; SHR-1603 from Jiangsu HengRui Medincine Co.; and SRF231 from Surface Oncology. Bispecific monoclonal antibodies are also available, such as IBI-322, targeting both CD47 and PD-L1 from Innovent Biologics. Antibodies against SIRPa are also possible, such as ALX148 from Alx Oncology; B1 765063 (OSE-172) from OSE; as well as small molecule inhibitors, such as RRx-001 (1-bromoacetyl- 3,3 dinitroazetidine) from EpicentRx and Azelnidipine (CAS number 7) or pharmaceutically acceptable salts thereof. See also Table 4 for further description of exemplary agents.
Company Approach Agent/Program Akesobio Australia Pty Ltd CD47 mAb AK117 Arch Oncology (Tioma Therapeutics) CD47 mAb A0-176 Elpiscience Biopharma Inc. CD47 ES004 EpicentRx Small molecule inhibitor RRx-001 of dinitroazetidine (1-bromoacetyl-3,3 hypoxia sensor to dinitroazetidine) downregulate CD47/SlRPct ImmuneOncia Therapeutics CD47 mAb human IMC-002 Innovent Biologics CD47 mAb IBI-188 (CD47 mAb) CD47/PD-L1 bispecific IBI-322 (Bispecific) mAb OSE SIRPct mAb B1765063 (OSE-172) Zai Lab CD47 mAb ZL-1201 Aix Oncology High-affinity SIRPa-Fc ALX148 Gilead/Forty Seven CD47 mAb Magrolimab F SI-SlRPot mAb I-Mab Biopharma CD47 mAb TJC4 Jiangsu HengRui Medicine Co., Ltd. CD47 mAb SHR-1603 Surface Oncology CD47 mAb human SRF231 Morphiex CD47 targeting MBT-001 phosphorodiamidate morpholino oligomers [0245] A0-176, in addition to inducing tumor phagocytosis through blocking the SIRPa interaction, is reported to preferentially bind tumor cells versus normal cells (particularly RBCs where binding is negligible) and directly kills tumor versus normal cells.
[0246] According to certain aspects, a SIRPa reagent may include the portion of SIRPa that is sufficient to bind CD47 at a recognizable affinity, which normally lies between the signal sequence and the transmembrane domain, or a fragment thereof that retains the binding activity.
A suitable S1RPa reagent reduces (e.g., blocks, prevents, etc.) the interaction between the native proteins S1RPa and CD47. For example, the CD47 blocking agent used in various aspects of the invention may be any of those disclosed in U.S. Patent No. 9,969,789 including but not limited to the S1RPa-IgG Fc fusion proteins disclosed therein, such as TTI-621 and TTI-622, both of which preferentially bind CD47 on tumor cells while also engaging activating Fc receptors. A
SERPa-IgG Fc fusion protein including the amino acid sequence SEQ ID NO:116, SEQ ID
NO:117, or SEQ ID NO:118 may, for example, be used.
[0247] Therapeutically effective doses of an anti-CD47 antibody or other protein CD47 inhibitor may be a dose that leads to sustained serum levels of the protein of about 40 pg/ml or more (e.g., about 50 ug/ml or more, about 60 ug/ml or more, about 75 ug/ml or more, about 100 ug/ml or more, about 125 ug/ml or more, or about 150 ug/ml or more).
Therapeutically effective doses or administration of a CD47 blockade, such as an anti-CD47 antibody or SIRPa fusion protein or small molecule, include, for example, amounts of 0.05 - 10 mg/kg (agent weight/subject weight), such as at least 0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 1.5 mg/kg, 2.0 mg/kg, 2.5 mg/kg. 3.0 mg/kg, 3.5 mg/kg, 4.0 mg/kg, 4.5 mg/kg, 5.0 mg/kg, 5.5 mg/kg, 6.0 mg/kg, 6.5 mg/kg, 7.0 mg/kg, 7.5 mg/kg, 8.0 mg/kg, 8.5 mg/kg, 9.0 mg/kg; or not more than 10 mg/kg, 9.5 mg/kg, 9.0 mg/kg, 8.5 mg/kg, 8.0 mg/kg, 7.5 mg/kg, 7.0 mg/kg, 6.5 mg/kg, 6.0 mg/kg, 5.5 mg/kg, 5.0 mg/kg, 4.5 mg/kg, 4.0 mg/kg, 3.5 mg/kg, 3.0 mg/kg, 2.5 mg/kg, 2.0 mg/kg, 1.5 mg/kg, 1.0 mg/kg, or any combination of these upper and lower limits.
Therapeutically effective doses of a small molecule CD47 blockade such as those disclosed herein also, for example, include 0.01 mg/kg to 1,000 mg/kg and any subrange or value of mg/kg therein such as 0.01 mg/kg to 500 mg/kg or 0.05 mg/kg to 500 mg/kg, or 0.5 mg/kg to 200 mg/kg, or 0.5 mg/kg to 150 mg/kg, or 1.0 mg/kg to 100 mg/kg, or 10 mg/kg to 50 mg/kg.
[02481 According to certain aspects, the anti-CD47 agent is a soluble CD47 polypeptide that specifically binds SIRPa and reduces the interaction between CD47 on one cell (e.g., an infected cell) and S1RPa on another cell (e.g., a phagocytic cell). A suitable soluble CD47 polypeptide can bind SIRPa without activating or stimulating signaling through SIRPa because activation of SIRPa would inhibit phagocytosis. Instead, suitable soluble CD47 polypeptides facilitate the preferential phagocytosis of infected cells over non-infected cells. Those cells that express higher levels of CD47 (e.g., infected cells) relative to normal, non-target cells (normal cells) will be preferentially phagocytosed. Thus, a suitable soluble CD47 polypeptide specifically binds SIRPa without activating/stimulating enough of a signaling response to inhibit phagocytosis. In some cases, a suitable soluble CD47 polypeptide can be a fusion protein (for example, as described in U.S. Pub. No. 20100239579).
[0249] Advantageously, CD47 blockade can enhance the cy-totoxic and prophagocytotic effect of a radiolabeled targeting agent, such as a radiolabeled HER3 and/or HER2 targeting agent, while reducing the dose-limiting radiotoxicity of the targeting agent, thereby improving tolerability and permitting higher radiation doses of the targeting agent to be used/tolerated in the treatment of a subject.
[0250] EXAMPLES
[0251] Example 1: Production of radiolabeled HER3 targeting agent [0252] The 1-IER3 targeting agent, such as a monoclonal antibody against 1-IER3, may be labeled with Indium-111 ("An) or Actinium-225 (125Ac) according to procedures detailed in International Publication No. WO 2017/155937 and US Provisional Patent Application No.
63/042,651 filed December 9, 2019 titled "Compositions and methods for preparation of site-specific radioconjugates.-[0253] Radiolabeling: As example, the antibody may be conjugated to a chelator-bearing linker, for example, as described herein or in the preceding patent applications. An exemplary linker includes at least dodecane tetraacetic acid (DOTA), wherein a goal of the conjugation reaction is to achieve a DOTA-antibody ratio of 3:1 to 5:1. Chelation with the radionuclide "In or 225Ac may then be performed and efficiency and purity of the resulting or 225Ac-labeled anti-HER3 antibody may be determined by HPLC and iTLC.
[0254] An exemplary labeling reaction for 225AC is as follows: A reaction including 15[11 0.15M NH40Ac buffer, pH=6.5 and 24 (101ag) DOTA-anti-HER3 (5 mg/ml) may be mixed in an Eppendorf reaction tube, and 4uL 225Ac (10 tiCi) in 0.05 M HC1 subsequently added. The contents of the tube may be mixed with a pipette tip and the reaction mixture incubated at 37 C
for 90 min with shaking at 100 rpm. At the end of the incubation period, 3 [EL
of a 1mM DTPA
solution may be added to the reaction mixture and incubated at room temperature for 20 min to bind the unreacted 225AC into the 225Ac-DTPA complex. Instant thin layer chromatography with 10cm silica gel strip and 10mM EDTA/normal saline mobile phase may be used to determine the radiochemical purity of 225Ac-DOTA-anti-HER3 through separating 225Ac-labeled anti-HER3 (225 Ac-DOTA-anti-FTER3) from free 225Ac (225Ac-DTPA). In this system, the radiolabeled antibody stays at the point of application and 225Ac-DTPA moves with the solvent front. "[he strips may be cut in halves and counted in the gamma counter equipped with the multichannel analyzer using channels 72-110 for 225Ac to exclude its daughters.
[0255] Purification: An exemplary radiolabeled HER3 targeting agent, such as 225Ac-DOTA-anti-HER3, may be purified either on PD10 columns pre-blocked with 1% HSA
or on Vivaspin centrifugal concentrators with a 50 kDa MW cut-off with 2 x 1.5 mL
washes, 3 min per spin. HPLC analyses of the 225Ac-DOTA-anti-HER3 after purification may be conducted using a Waters HPLC system equipped with flow-through Waters UV and Bioscan Radiation detectors, using a TSK3000SW XL column eluted with PBS at pH=7.4 and a flow rate of lml/min.
[0256] Stability determination: An exemplary radiolabeled HER3 targeting agent, such as 225Ac-DOTA-anti-HER3, may be used for stability determination, wherein the 225Ac-DOTA-anti-HER3 may be tested either in the original volume or diluted (2-10 fold) with the working buffer (0.15 M NI-140Ac) and incubated at room temperature (rt) for 48 hours or at 4 C for 96 hours and tested by ITLC. Stability is determined by comparison of the intact radiolabeled anti-HER3 before and after incubation. Other antibodies labeled with 225AC have been found to be stable at 4 C for up to 96 hrs.
[0257] Immunoreactivity (IR) determination: An exemplary radiolabeled HER3 targeting agent, such as 225Ac-DOTA-anti-HER3, may be used in immunoreactivity experiments. HER3 positive cells and control HER3 negative cells may be used in the amounts of 1.0-7.5 million cells per sample to investigate the amount of binding (percent radioactivity binding to cells after several washes; or using an immunoreactive fraction (IRE) bead assay may be performed according to methods disclosed in as described by Sharma, 2019) Prior assays for other antibodies radiolabeled with "In or 225Ac demonstrated about 50-60%
immunoreactivity.
[0258] EXAMPLE 2¨ Exemplary PARPi administration and dosing regimes [0259] (A) Olaparib (Lynparza ) - Normal and Reduced Dosing Regimens [0260] Olaparib is sold by Astra7eneca under the brand name Lynparza .
Lynparza is sold in tablet form at 100 mg and 150 mg. The dosage is 300 mg taken orally twice daily for a daily total of 600 mg Dosing continues until disease progression or unacceptable toxicity. This dosing regimen is referred to herein as the "normal" human dosing regimen for Lynparza , regardless of the disorder treated. Any dosing regimen having a shorter duration (e.g., 21 days) or involving the administration of less Lynparza (e.g., 300 mg/day) is referred to herein as a -reduced" human dosing regimen. Examples of reduced human dosing regimens include the following: (i) 550 mg/day; (ii) 500 mg/day; (iii) 450 mg/day; (iv) 400 mg/day;
(v) 350 mg/day;
(vi) 300 mg/day; (vii) 250 mg/day; (viii) 200 mg/day; (ix) 150 mg/day; (x) 100 mg/day; or (xi) 50 mg/day.
[0261] (B) Niraparib (Zejula ) - Normal and Reduced Dosing Regimens [0262] Niraparib is sold by Tesaro under the brand name Zejula . Zejula is sold in capsule form at 100 mg. The dosage is 300 mg taken orally once daily. Dosing continues until disease progression or unacceptable adverse reaction. This dosing regimen is referred to herein as the "normal" human dosing regimen for Zejula , regardless of the disorder treated. Any dosing regimen having a shorter duration (e.g., 21 days) or involving the administration of less Zejula (e.g., 150 mg/day) is referred to herein as a -reduced" human dosing regimen.
Examples of reduced human dosing regimens include the following: (i) 250 mg/day; (ii) 200 mg/day; (iii) 150 mg/day; (iv) 100 mg/day; or (v) 50 mg/day.
[0263] (C) Rucaparib (Rubracat) - Normal and Reduced Dosing Regimens [0264] Rucaparib is sold by Clovis Oncology, Inc. under the brand name RubracaTM.
RubracaTM is sold in tablet form at 200 mg and 300 mg. The dosage is 600 mg taken orally twice daily for a daily total of 1,200 mg. Dosing continues until disease progression or unacceptable toxicity. This dosing regimen is referred to herein as the "normal" human dosing regimen for RubracaTM, regardless of the disorder treated. Any dosing regimen having a shorter duration (e.g., 21 days) or involving the administration of less RubracaTM
(e.g., 600 mg/day) is referred to herein as a "reduced" human dosing regimen. Examples of reduced human dosing regimens include the following: (i) 1,150 mg/day; (ii) 1,100 mg/day; (iii) 1,050 mg/day; (iv) 1,000 mg/day; (v) 950 mg/day; (vi) 900 mg/day; (vii) 850 mg/day; (viii) 800 mg/day; (ix) 750 mg/day; (x) 700 mg/day; (xi) 650 mg/day; (xii) 600 mg/day; (xiii) 550 mg/day;
(xiv) 500 mg/day; (xv) 450 mg/day; (xvi) 400 mg/day; (xvii) 350 mg/day; (xviii) 300 mg/day; (xix) 250 mg/day; (xx) 200 mg/day; (xxi) 150 mg/day; or (xxii) 100 mg/day.
[0265] (D) ¨ Talazoparib (TalzennalM) - Normal and Reduced Dosing Regimens [0266] Talazoparib is sold by Pfizer Labs under the brand name TalzennaTM.
TalzennaTM is sold in capsule form at 1 mg. The dosage is 1 mg taken orally.
Dosing continues until disease progression or unacceptable toxicity. This dosing regimen is referred to herein as the "normal" human dosing regimen for TalzennaTM, regardless of the disorder treated. Any dosing regimen having a shorter duration (e.g., 21 days) or involving the administration of less TalzennaTM (e.g., 0.5 mg/day) is referred to herein as a "reduced" human dosing regimen.
Examples of reduced human dosing regimens include the following: (i) 0.9 mg/day; (ii) 0.8 mg/day; (iii) 0.7 mg/day; (iv) 0.6 mg/day; (v) 0.5 mg/day; (vi) 0.4 mg/day;
(vii) 0.3 mg/day;
(viii) 0.2 mg/day; or (ix) 0.1 mg/day.
[0267] EXAMPLE 3: Dosing regimens for HER3 targeting agent and PARPi [0268] A human patient may be treated according to the following regimen. One of olaparib, niraparib, rucaparib or talazoparib (PARPi) is orally administered according to one of the dosing regimens listed in Example 2, accompanied by intravenous administration of a radiolabeled 1-1ER3 targeting agent as detailed herein in either single or fractional administration.
For example, the dosing regimens include, by way of example: (a) the PARPi and the 1-IER3 targeting agent administered concurrently, wherein (i) each is administered beginning on the same day, (ii) the HER3 targeting agent is administered in a single dose or fractionated doses not less than one week apart, and (iii) the PARPi is administered daily or twice daily (as appropriate), and for a duration equal to or exceeding that of the HER3 targeting agent administration; or (b) the PARPi and HER3 targeting agent are administered concurrently, wherein (i) the PARPi administration precedes HER3 targeting agent administration by at least one week, (ii) the HER3 targeting agent is administered in a single dose or fractionated doses not less than one week apart, and (iii) the PARPi is administered daily or twice daily (as appropriate), and for a duration equal to or exceeding that of the HER3 targeting agent administration.
[0269] EXAMPLE 4: Dosing regimens for HER3 targeting agent and a CD47 Blockade.
[0270] According to certain aspects of the present invention, the CD47 blocking agent may, for example, be a monoclonal antibody that prevents CD47 binding to SlRPa. Exemplary protein CD47 blockades include magrolimab, lemzoparlimab, A0-176, TTI-621, TTI-622, or a combination thereof. The CD47 blockade may alternatively, or additionally, include agents that modulate the expression of CD47 and/or SIRPa, such as phosphorodiamidate morpholino oligomers (PMO) that block translation of CD47 such as MBT-001 (PMO, morpholino, Sequence: 5'-CGTCACAGGCAGGACCCACTGCCCA-3) [SEQ ID NO:114]) or any of the PMO oligomer CD47 inhibitors disclosed in any of U.S. Patent No. 8,557,788, US, Patent No.
8,236,313, U.S. Patent No. 10,370,439 and lnt'l Pub. No. W02008060785.
'therapeutically effective doses of anti-CD47 antibodies include at least 0.05 ¨ 10 mg/kg Thus, methods of the present invention may include administering one or more of the anti-CD47 antibodies or other agents, accompanied by intravenous administration of a radiolabeled HER3 targeting agent as detailed herein in either single or fractional administration. For example, the dosing regimens include, by way of example: (a) the anti-CD47 antibody or agent and the 1-IE,R3 targeting agent administered concurrently, wherein (i) each is administered beginning on the same day, (ii) the HER3 targeting agent is administered in a single dose or fractionated doses not less than one week apart, and (iii) the anti-CD47 antibody or agent is administered daily or twice daily (as appropriate), and for a duration equal to or exceeding that of the HER3 targeting agent administration; or (b) the anti-CD47 antibody or agent and HER3 targeting agent are administered concurrently, wherein (i) the anti-CD47 antibody or agent administration precedes HER3 targeting agent administration by at least one week, (ii) the HER3 targeting agent is administered in a single dose or fractionated doses not less than one week apart, and (iii) the anti-CD47 antibody or agent is administered daily or twice daily (as appropriate), and for a duration equal to or exceeding that of the HER3 targeting agent administration.
[0271] EXAMPLES: Dosing regimens for HER3 targeting agent and an ICI.
[0272] According to certain aspects of the present invention, the immune checkpoint inhibitor (ICI) may be a monoclonal antibody against any of PD-1, PD-L1, PD-L2, CTLA-4, CD137. Therapeutically effective doses of these antibodies include at least 0.05 ¨ 10 mg/kg.
Thus, method of the present invention include administering one or more ICI, accompanied by intravenous administration of a radiolabeled HER3 targeting agent as detailed herein in either single or fractional administration. For example, the dosing regimens include, by way of example: (a) the ICI and the HER3 targeting agent administered concurrently, wherein (i) each is administered beginning on the same day, (ii) the HER3 targeting agent is administered in a single dose or fractionated doses not less than one week apart, and (iii) the ICI is administered daily or twice daily (as appropriate), and for a duration equal to or exceeding that of the HER3 targeting agent administration; or (b) the ICI and HER3 targeting agent are administered concurrently, wherein (i) the anti-CD47 antibody administration precedes HER3 targeting agent administration by at least one week, (ii) the HER3 targeting agent is administered in a single dose or fractionated doses not less than one week apart, and (iii) the ICI is administered daily or twice daily (as appropriate), and for a duration equal to or exceeding that of the 1-IER3 targeting agent administration, [0273] Without limitation, the following aspects are also provided by this disclosure:
[0274] Aspect 1. A method for treating a solid cancer in a mammalian subject such as a human patient, the method including: administering to the subject a therapeutically effective amount of a radiolabeled HER3 targeting agent.
[0275] Aspect 2. The method according to any preceding aspect, wherein the solid cancer is a breast cancer, gastric cancer, bladder cancer, cervical cancer, endometrial cancer, skin cancer, stomach cancer, testicular cancer, esophageal cancer, bronchioloalveolar cancer, prostate cancer, colorectal cancer, ovarian cancer, cervical epidermoid cancer, pancreatic cancer, lung cancer, renal cancer, head and neck cancer, or any combination thereof [0276] Aspect 3. The method according to any preceding aspect, wherein the solid cancer is colorectal cancer, gastric cancer, ovarian cancer, non-small cell lung carcinoma, head and neck squamous cell cancer, pancreatic cancer, renal cancer, or any combination thereof.
[0277] Aspect 4. The method according to any preceding aspect, wherein the solid cancer is a HER3-positive cancer such as a 1-lER3-positive solid tumor.
[0278] Aspect 5. The method according to any preceding aspect, wherein the radiolabeled HER3 targeting agent includes a radiolabel selected from 13115 12515 12315 90y5 177Lu5 186Re5 188Re5 89sr, 153sm5 32p5 225Ac5 213Bi5 213p05 211At5 212Bi5 213Bi5 223Ra5 227Th, 149Tb5 137cs, 212=s+ 5 YID 1 3Pd, or any of those disclosed herein, or any combination thereof.
[0279] Aspect 6. The method according to any preceding aspect, wherein the radiolabeled HER3 targeting agent includes a radiolabel selected from 1-31I
90Y, 177Lu, 225Ac, 213Bi, 211A.t, 213Bi, 227Th, 212Pb, or any combination thereof.
[0280] Aspect 7. The method according to any preceding aspect, wherein the radiolabeled HER3 targeting agent includes an antibody against HER3.
[0281] Aspect 8. The method according to any preceding aspect, wherein the targeting agent includes an anti-HER3 monoclonal antibody such as any of those disclosed herein, such as a HER3 antibody selected from Patritumab, Seribantumab (MM-121), Lumretuzumab, Elgemtumab, GSK2849330, and AV-203 and any combination thereof.
[0282] Aspect 9. The method according to any preceding aspect, wherein the targeting agent includes a monoclonal antibody: (i) having a heavy chain sequence including SEQ ID NO:77 and/or a light chain sequence including SEQ ID NO:78; (ii) having an immunoglobulin heavy chain variable region including a CDR-H1 including SEQ ID
NO:15, a CDR-H2 including SEQ ID NO:16, and/or a CDR-H3 including SEQ ID NO:17, and/or an immunoglobulin light chain variable region including a CDR-L1 including SEQ ID
NO:18, a CDR-L2 including SEQ ID NO:19, and/or a CDR-L3 including SEQ ID NO:20; (iii) having an immunoglobulin heavy chain variable region including SEQ ID NO:21 and/or an immunoglobulin light chain variable region including SEQ ID NO:22; or (iv) having an immunoglobulin heavy chain amino acid sequence of SEQ ID NO:23 and/or an immunoglobulin light chain amino acid sequence of SEQ ID NO:24.
[0283] Aspect 10. The method according to any preceding aspect, wherein the targeting agent includes a monoclonal antibody including a heavy chain variable region having an amino acid sequence as set forth in SEQ. ID NO:7 and/or a light chain variable region having an amino acid sequence as set forth in SEQ. ID NO:8.
[0284] Aspect 11. The method according to any preceding aspect, wherein the targeting agent includes a monoclonal antibody including one or more of the heavy chain N-terminal region and complementarity determining regions (CDRs) having amino acid sequences as set forth in SEQ. ID NO:13 and/or 1-3, respectively; and/or including one or more of the light chain N-terminal region and CDRs having amino acid sequences as set forth in SEQ. ID NO:14 and/or 4-6, respectively.
[02851 Aspect 12. The method according to any preceding aspect, wherein the effective amount of the radiolabeled HER3 targeting agent is a maximum tolerated dose.
[02861 Aspect 13. The method according to any preceding aspect, wherein the radiolabeled HER3 targeting agent is 225A 177LU-, or 1311-labeled.
[02871 Aspect 14. The method according to any preceding aspect, wherein the therapeutically effective amount of the radiolabeled HER3 targeting agent includes a single dose that delivers less than 2Gy, or less than 8 Gy, such as doses of 2 Gy to 8 Gy, to the subject.
[02881 Aspect 15. The method according to any preceding aspect, wherein the radiolabeled HER3 targeting agent is 'Ac-labeled, and the effective amount of the 'Ac-labeled HER3 targeting agent includes a dose of 0.1 to 50 uCi/kg body weight of the subject, or 0.2 to 20 uCi/kg body weight of the subject, or 0.5 to 10 uCi/kg subject body weight.
[02891 Aspect 16. The method according to any preceding aspect, wherein the radiolabeled HER3 targeting agent is a full-length antibody against HER3 that is 225Ac-labeled, and the effective of the 'Ac-labeled HER3 targeting agent includes less than 5 uCi/kg body weight of the subject, such as 0.1 to 5 uCi/kg body weight of the subject.
[02901 Aspect 17. The method according to any one of aspects 1 to 6, wherein the radiolabeled HER3 targeting agent is an antibody fragment, such as a minibody or nanobody against HER3 that is 'Ac-labeled, and the effective of the 'Ac-labeled HER3 targeting agent includes greater than 5 uCi/kg body weight of the subject, such as 5 to 20 uCi/kg body weight of the subject.
[0291] Aspect 18. The method according to any one of aspects 1 to 14, wherein the radiolabeled HER3 targeting agent is 225Ac-labeled, and the effective amount of the l'Ac-labeled HER3 targeting agent includes 2 ILICi to 2mCi, or 2 LICi to 250 [iCi, or 75 tCi to 400 pCi.
[0292] Aspect 19. The method according to any one of aspects 1 to 14, wherein the radioisotope labeled HER3 targeting agent is 177Lu-labeled and the effective amount of the EIER3 targeting agent includes a dose of less than 1000 uCi/kg body weight of the subject, such as a dose of 1 to 900 uCi/kg body weight of the subject, or 5 to 250 uCi/kg body weight of the subject or 50 to 450 uCi/kg body weight.
[02931 Aspect 20. The method according to any one of aspects 1 to 14, wherein the radioisotope labeled HER3 targeting agent is 177Lu-labeled, and the effective amount of the '77Lu-labeled HER3 targeting agent includes a dose of 10 mCi to at or below 30 mCi, or from at least 100 pCi to at or below 3 mCi, or from 3 mCi to at or below 30 mCi.
[0294] Aspect 21. The method according to any one of aspects 1 to 14, wherein the radiolabeled HER3 targeting agent is 131I-labeled, and the effective amount of the 131I-labeled HER3 targeting agent includes a dose of less than 1200 mCi, such as a dose of 25 to 1200 mCi, or 100 to 400 mCi, or 300 to 600 mCi, or 500 to 1000 mCi.
[0295] Aspect 22. The method according to any one of aspects 1 to 14, wherein the radiolabeled HER3 targeting agent is 131I-labeled, and the effective amount of the 131I-labeled fIER3 targeting agent includes a dose of less than 200 mCi, such as a dose of 1 to 200 mCi, or 25 to 175 mCi, or 50 to 150 mCi.
10296] Aspect 23. The method according to any preceding aspect, wherein the effective amount of the HER3 targeting agent includes a protein dose of less than 3 mg/kg body weight of the subject, such as from 0.001 mg/kg patient weight to 3.0 mg/kg patient weight, or from 0.005 mg/kg patient weight to 2.0 mg/kg patient weight, or from 0.01 mg/kg patient weight to 1 mg/kg patient weight, or from 0.1 mg/kg patient weight to 0.6 mg/kg patient weight, or 0.3 mg/kg patient weight, or 0.4 mg/kg patient weight, or 0.5 mg/kg patient weight, or 0.6 mg/kg patient weight [0297] Aspect 24. The method according to any preceding aspect, wherein the targeting agent is administered according to a dosing schedule selected from the group consisting of once every 7, 10, 12, 14, 20, 24, 28, 36, and 42 days throughout a treatment period, wherein the treatment period includes at least two doses.
[0298] Aspect 25. The method according to any one of aspects 1 to 6, wherein the HER3 targeting agent is a peptide or small molecule.
[0299] Aspect 26. The method according to any preceding aspect, further including administering to the subject a therapeutically effective amount of an immune checkpoint therapy, a chemotherapeutic agent, a DNA damage response inhibitor (DDRi), a CD47 blockade, or a combination thereof.
[0300] Aspect 27. The method according to aspect 26, wherein the immune checkpoint therapy includes an antibody or other blocking agent against CTLA-4, PD-1, TIM-3, VISTA, BTLA, LAG-3, TIGIT, CD28, 0X40, GITR, CD137, CD40, CD4OL, CD27, HVEM, PD-L1, PD-L2, PD-L3, PD-L4, CD80, CD86, CD137-L, GITR-L, CD226, B7-H3, B7-H4, BTLA, TIGIT, GALS, K1R, 2B4, CD160, or CGEN-15049, or any combination of such antibodies and blocking agents.
[0301] Aspect 28. The method according to aspect 27, wherein the immune checkpoint therapy includes an antibody against PD-1, PD-L1, PD-L2, CTLA-4, CD137, or a combination thereof.
[0302] Aspect 29. The method according to aspect 26, wherein the DDRi includes a poly(ADP-ribose) polymerase inhibitor (PARPi), an ataxia telangiectasia mutated inhibitor (ATMi), an ataxia talangiectasia mutated and Rad-3 related inhibitor (ATRi), or a Weel inhibitor.
[0303] Aspect 30. The method according to aspect 29, wherein the PARPi includes one or more of olaparib, niraparib, rucaparib and talazoparib.
[0304] Aspect 31. The method according to aspect 29, wherein the ATMi includes one or more of KU-55933, KU-59403, wortmannin, CP466722, or KU-60019.
[0305] Aspect 32. The method according to aspect 29, wherein the ATRi includes one or more of Schisandrin B, NU6027, NVP-BEA235, VE-821, VE-822, AZ20, or AZD6738.
[0306] Aspect 33. The method according to aspect 29, wherein the Weel inhibitor includes AZD-1775 (i.e., adavosertib).
[0307] Aspect 34. The method according to aspect 26, wherein the CD47 blockade includes an agent, such as a monoclonal antibody that prevents CD47 binding to S1RPa and/or an agent that modulates CD47 expression.
[0308] Aspect 35: The method according to aspect 34, wherein the CD47 blockade includes one or more of magrolimab, lemzoparlimab, A0-176, TTI-621, TTI-622, or a combination thereof; and/or wherein the agent that modulates CD47 expression includes phosphorodiamidate morpholino oligomers (PMO) that reduce expression of CD47 (e.g., MET-001).
[0309] Aspect 36: The method according to aspect 34, wherein the therapeutically effective amount of the CD47 blockade includes 0.05 to 5 mg/Kg patient weight [0310] Aspect 37. The method according to aspect 26, wherein the HER3 targeting agent is administered at least one week before the immune checkpoint therapy and/or the DDRi and/or the CD47 blockade; or wherein the immune checkpoint therapy and/or the DDRi and/or CD47 blockade is administered at least one week before the HER3 targeting agent.
[0311] Aspect 38. The method according to aspect 26, wherein the HER3 targeting agent is administered with one of the immune checkpoint therapy or the DDRi or the CD47 blockade, and the other of the immune checkpoint therapy or the DDRi or the CD47 blockade is administered either before or after the HER3 targeting agent.
[0312] Aspect 39. The method according to aspect 26, wherein the HER3 targeting agent is administered simultaneously with the immune checkpoint therapy and/or the DDRi and/or the CD47 blockade.
[0313] Aspect 40. The method according to any preceding aspect, wherein the targeting agent is a multi-specific antibody, wherein the multi-specific antibody includes: a first target recognition component which specifically binds to an epitope of HER3, and a second target recognition component which specifically binds to a different epitope of 1-LER3 than the first target recognition component, or an epitope of a different antigen.
[0314] Aspect 41. The method according to aspect 40, wherein the HER3 targeting agent includes a bispecific antibody against FIER3/HER2 such as MM-111 or MCLAO-128, or against IGF-1R/HER3 such as MM-141 (i.e., Istiratumab), and/or against HER1/HER3 such as MEHD7945A (i.e., Duligotumab).
[0315] Aspect 42. A method for treating a proliferative disease or disorder, the method including: diagnosing the subject with HER3-positive cells; and if the subject has HER3-positive cells, administering to the subject a therapeutically effective amount of an HER3 targeting agent according to any of the methods of aspects 1 to 41.
[0316] Aspect 43. The method according to aspect 42, wherein the diagnosing includes obtaining a sample of blood or tissue from the subject; mounting the sample on a substrate; and detecting the presence or absence of HER3 antigen using a diagnostic antibody, wherein the diagnostic antibody includes an antibody against HER3 labeled with a radiolabel such as 3H, 14c, 3213, 35S, and 12571; fluorescent or chemiluminescent compounds, such as fluorescein isothiocyanate, rhodamine, or luciferin; or an enzyme, such as alkaline phosphatase, 3-gal actosidase, or horseradish peroxidase.
[0317] Aspect 44. The method according to aspect 42, wherein the diagnosing includes administering a HER3 targeting agent to the subject, wherein the HER3 targeting agent includes isF, , a radiolabel selected from the group including 6sGa, 64cu , g9zr, , 124- 99mTc, or 111In;
waiting a time sufficient to allow the HER3 targeting agent to accumulate at a tissue site, and imaging the tissues with a non-invasive imaging technique to detect presence or absence of HER3-positive cells.
[0318] Aspect 45. The method according to aspect 44, wherein the non-invasive imaging technique includes positron emission tomography (PET imaging) for isF, tic, 68,6a, 64cu, 89Zr, or 124I labeled HER3 targeting agents or single photon emission computed tomography (SPECT
imaging) for 99"1Tc or 111-In labeled HER3 targeting agents.
[0319] While various specific embodiments have been illustrated and described herein, it will be appreciated that various changes can be made without departing from the spirit and scope of the invention(s). Moreover, features described in connection with one aspect of the invention may be used in conjunction with other aspects of the invention, even if not explicitly exemplified in combination within.
[0320] References [0321] Mishra R, Patel H, Alanazi S, Yuan L, Garrett JT. HER3 signaling and targeted therapy in cancer. Oncol Rev. 2018;12(1).
[0322] Meneses-Lorente G, Friess T, Kolm I, et al. Preclinical pharmacokinetics, pharmacodynamics, and efficacy of RG7116: a novel humanized, glycoengineered anti-1-IER3 antibody. Cancer Chemother Pharmacol. 2015;75(4):837-850.
[0323] Mirschberger C, Schiller CB, Schraml M, et al. RG7116, a Therapeutic Antibody That Binds the Inactive HER3 Receptor and Is Optimized for Immune Effector Activation.
Cancer Res. 2013;73(16):5183-5194.
[0324] Meulendijks D, Jacob W, Martinez-Garcia M, et al. First-in-Human Phase 1 Study of Lumretuzumab, a Glycoengineered Humanized Anti-HER3 Monoclonal Antibody, in Patients with Metastatic or Advanced HER3-Positive Solid Tumors. Clin Cancer Res.
2016;22(4):877-885.
[0325] Reynolds KL, Bedard PL, Lee S-H, et al. A phase I open-label dose-escalation study of the anti-FIER3 monoclonal antibody LJM716 in patients with advanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer.
BMC Cancer. 2017;17(1):646.
The effective amount of 225Ac-labeled HER3 targeting agent may be at least 2 pCi, such as at least 5 pCi, 10 pCi, 20 pCi, 30 pCi, 40 pCi, 50 pCi, 60 pCi, 70 pCi, 80 pCi, 90 pCi, 100 pCi, 200 pCi, 300 pCi, 400 pCi, 500 pCi, 600 pCi, 700 pCi, 800 pCi, 900 pCi, 1 mCi, 1.1 mCi, 1,2 mCi, 1.3 mCi, 1.4 mCi, or 1.5 mCi. According to certain aspects, the 225Ac-labeled HER3 targeting agent may be administered at a dose that includes any combination of upper and lower limits as described herein, such as from at least 2 tiCi to at or below 1mCi, or from at least 2 pCi to at or below 250 pCi, or from 75 pCi to at or below 400 [0066] According to certain aspects, the 225Ac-labeled HER3 targeting agent includes a single dose that delivers less than 12Gy, or less than 8 Gy, or less than 6 Gy, or less than 4 Gy, or less than 2 Gy, such as doses of 2 Gy to 8 Gy, to the subject, such as predominantly to the targeted solid tumor.
[00671 According to certain aspects, the HER3 targeting agent may be an antibody, peptide, or small molecule radiolabeled with 177Lu ("177Lu-labeled"), and the effective amount may be, for example, below 1 mCi/kg (i.e., where the amount of 177Lu-labeled antibody administered to the subject delivers a radiation dose of below 1000 nCi per kilogram of subject's body weight). According to certain aspects, when the antibody is 'Lu-labeled, the effective amount is below 900 pCi/kg, 800 nCi/kg, 700 pCi/kg, 600 p,Ci/kg, 500 pCi/kg, 400 pCi/kg, 300 litCi/kg, 200 1.1,Ci/kg, 150 laCi/kg, 100 nCi/kg, 80 nCi/kg, 60 pCi/kg, 50 IJ,Ci/kg, 40 IJ,Ci/kg, 30 pCi/kg, 20 pCi/kg, 10 [1,Ci/kg, 5 nCi/kg, or 1 nCi/kg. According to certain aspects, the effective amount of the 177Lu-labeled antibody is at least 1 pCi/kg, 2.5 pCi/kg, 5 pCi/kg, 10 !..iCi/kg, 20 pCi/kg, 30 pCi/kg, 40 pCi/kg, 50 pCi/kg, 60 pCi/kg, 70 pCi/kg, 80 pCi/kg, 90 pCi/kg, 100 pCi/kg, 150 pCi/kg, 200 pCi/kg, 250 pCi/kg, 300 pCi/kg, 350 pCi/kg, 400 pCi/kg or 450 pCi/kg.
According to certain aspects, an 177Lu-labeled antibody may be administered at a dose that includes any combination of upper and lower limits as described herein, such as from at least 5 mCi/kg to at or below 50 pCi/kg, or from at least 50 mCi/kg to at or below 500 pCi/kg.
[00681 According to certain aspects, the HER3 targeting agent may be an antibody that is 177Lu-labeled, and the effective amount may be below 45 mCi, such as below 40 mCi, 30 mCi, mCi, 10 mCi, 5 mCi, 3.0 mCi, 2.0 mCi, 1.0 mCi, 800 põCi, 600 pCi, 400 pCi, 200 nCi, 100 pCi, or 50 pCi. The effective amount of 177Lu-labeled HER3 targeting agent may be at least 10 pCi, such as at least 25 pCi, 50 nCi, 100 pCi, 200 pCi, 300 pCi, 400 pCi, 500 pCi, 600 pCi, 700 pCi, 800 pCi, 900 pCi, 1 mCi, 2 mCi, 3 mCi, 4 mCi, 5 mCi, 10 mCi, 15 mCi, 20 mCi, 25 mCi, 30 mCi. According to certain aspects, an 177Lu-labeled antibody may be administered at a dose that includes any combination of upper and lower limits as described herein, such as from at least 10 mCi to at or below 30 mCi, or from at least 100 pCi to at or below 3 mCi, or from 3 mCi to at or below 30 mCi.
[00691 According to certain aspects, the HER3 targeting agent may be an antibody, peptide, or small molecule radiolabeled with 1311 ("1_311-labeler), and the effective amount may be below, for example, 1200 mCi (i.e., where the amount of 131I administered to the subject delivers a total body radiation dose of below 1200 mCi in a non-weight-based dose). According to certain aspects, the effective amount of the 131I-labeled targeting agent may be below 1100 mCi, below 1000 mCi, below 900 mCi, below 800 mCi, below 700 mCi, below 600 mCi, below 500 mCi, below 400 mCi, below 300 mCi, below 200 mCi, below 150 mCi, or below 100 mCi.
According to certain aspects, the effective amount of the 'I-labeled targeting agent may be below 200 mCi, such as below 190 mCi, 180 mCi, 170 mCi, 160 mCi, 150 mCi, 140 mCi, 130 mCi, 120 mCi, 110 mCi, 100 mCi, 90 mCi, 80 mCi, 70 mCi, 60 mCi, or 50 mCi.
According to certain aspects, the effective amount of the 134-labeled targeting agent may be at least 1 mCi, such as at least 2 mCi, 3 mCi, 4 mCi, 5 mCi, 6 mCi, 7 mCi, 8 mCi, 9 mCi, 10 mCi, 20 mCi, 30 mCi, 40 mCi, 50 mCi, 60 mCi, 70 mCi, 80 mCi, 90 mCi, 100 mCi, 110 mCi, 120 mCi, 130 mCi, 140 mCi, 150 mCi, 160 mCi, 170 mCi, 180 mCi, 190 mCi, 200 mCi, 250 mCi, 300 mCi, 350 mCi, 400 mCi, 450 mCi, 500 mCi. According to certain aspects, an "II-labeled targeting agent may be administered at a dose that includes any combination of upper and lower limits as described herein, such as from at least 1 mCi to at or below 100 mCi, or at least 10 mCi to at or below 200 mCi.
[0070] While select radionuclides are discussed in detail herein, any, such as any disclosed herein, may be used for radiolabeled targeting agents, such as a radiolabeled HER3 targeting agent as disclosed herein.
[00711 As used herein, a composition including a HER3 targeting agent includes a -patient specific composition" that includes both a radionuclide labeled portion and an unlabeled portion. According to certain aspects of the present invention, when the HER3 targeting agent is labeled with a radioisotope, the majority of the targeting agent (antibody, antibody fragment, etc.) administered to a patient may consist of unlabeled targeting agent, with the minority being the radiolabeled targeting agent. The ratio of labeled to non-labeled targeting agent can be adjusted using known methods. According to certain aspects of the present invention, the patient specific composition may include the HER3 targeting agent in a ratio of labeled : unlabeled HER3 targeting agent of from about 0.01:10 to 1:1, such as 0.1:10 to 1:1 labeled: unlabeled.
[0072] Accordingly to certain aspects of the present invention, the HER3 targeting agent may be provided in a total protein or peptide amount of up to 100mg, such as up to 60 mg, such as 5mg to 45mg, or a total protein amount of from 0.001 mg/kg patient weight to 3.0 mg/kg patient weight, such as from 0.005 mg/kg patient weight to 2.0 mg/kg patient weight, or from 0.01 mg/kg patient weight to 1 mg/kg patient weight, or from 0.1 mg/kg patient weight to 0.6 mg/kg patient weight, or 0.3 mg/kg patient weight, or 0.4 mg/kg patient weight, or 0.5 mg/kg patient weight, or 0.6 mg/kg patient weight.
[0073] The inventive combination of a radiolabeled fraction and an unlabeled fraction of the antibody or other targeting agent allows the composition to be tailored to a specific patient, wherein each of the radiation dose and the protein dose of the antibody or other targeting agent are personalized to that patient based on at least one patient-specific parameter. As such, each vial of the composition may be made for a specific patient, where the entire content of the vial is delivered to that patient in a single dose. When a treatment regime calls for multiple doses, each dose may be formulated as a patient specific dose in a vial to be administered to the patient as a "single dose" (i.e., full contents of the vial administered at one time). The subsequent dose may be formulated in a similar manner, such that each dose in the regime provides a patient specific dose in a single dose container. One of the advantages of such a composition is that there will be no left-over radiation that would need to be discarded or handled by the medical personnel, e.g., no dilution, or other manipulation to obtain a dose for the patient. When provided in a single dose container, the container may simply be placed in-line in an infusion tubing set for infusion to the patient Moreover, the volume can be standardized so that there is a greatly reduced possibility of medical error (i.e., delivery of an incorrect dose, as the entire volume of the composition is to be administered in one infusion).
[0074] Thus, according to certain aspects, the HER3 targeting agent may be provided as a single dose composition which may be tailored to a specific patient, wherein the amount of radiolabeled and unlabeled 1-lER3 targeting agent in the composition may depend on one or more of a patient weight, age, gender, disease state and/or health status, such as detailed in International Publication No. WO 2016/187514 and U.S. Patent No. 10,736,975.
According to certain aspects, the HER3 targeting agent may be provided as a multi-dose therapeutic, wherein each dose in the treatment regime is provided as a patient specific composition The patient-specific composition includes radiolabeled and unlabeled HER3 targeting agents, wherein the amounts of each depend on one or more of patient weight, age, gender, disease state, and/or health status.
[0075] As used herein, the terms "subject" and "patient" are interchangeable and include, without limitation, a mammal such as a human, a non-human primate, a dog, a cat, a horse, a sheep, a goat, a cow, a rabbit, a pig, a rat and a mouse. Where the subject is human, the subject may be of any age. For example, the subject can be 60 years or older, 65 or older, 70 or older, 75 or older, 80 or older, 85 or older, or 90 or older. Alternatively, the subject can be 50 years or younger, 45 or younger, 40 or younger, 35 or younger, 30 or younger, 25 or younger, or 20 or younger. For a human subject afflicted with cancer, the subject can be newly diagnosed, or relapsed and/or refractory, or in remission.
[0076] As used herein, "treating" a subject afflicted with a cancer shall include, without limitation, (i) slowing, stopping or reversing the cancer's progression, (ii) slowing, stopping or reversing the progression of the cancer's symptoms, (iii) reducing the likelihood of the cancer's recurrence, and/or (iv) reducing the likelihood that the cancer's symptoms will recur. According to certain preferred aspects, treating a subject afflicted with a cancer means (i) reversing the cancer's progression, ideally to the point of eliminating the cancer, and/or (ii) reversing the progression of the cancer's symptoms, ideally to the point of eliminating the symptoms, and/or (iii) reducing or eliminating the likelihood of relapse (i.e., consolidation, which ideally results in the destruction of any remaining cancer cells).
[0077] "Chemotherapeutic-, in the context of this invention, shall mean a chemical compound which inhibits or kills growing cells and which can be used or is approved for use in the treatment of cancer. Exemplary chemotherapeutic agents include cytostatic agents which prevent, disturb, disrupt or delay cell division at the level of nuclear division or cell plasma division. Such agents may stabilize microtubules, such as taxanes, in particular docetaxel or paclitaxel, and epothilones, in particular epothilone A, B, C, D, E, and F, or may destabilize microtubules such as vinca alkaloids, in particular vinblastine, vincristine, vindesine, vinflunine, and vinorelbine. Exemplary chemotherapeutics also include radiosensitizers that may synergize with the radiolabeled 1-IER3, such as temozolomide, cisplatin, and/or fluorouracil.
[0078] "Therapeutically effective amount" or "effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. A
therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic or combination of therapeutics include, for example, improved well-being of the patient, reduction in a tumor burden, arrested or slowed growth of a tumor, and/or absence of metastasis of cancer cells to other locations in the body. According to certain aspects, "therapeutically effective amount" or "effective amount" refers to an amount of the radiolabeled HER3 targeting agent that may deplete or cause a reduction in the overall number of cells expressing HER3 and/or that may inhibit growth of cells expressing HER3, when used alone or in combination or conjunction with other agents and/treatment modalities.
[0079] As used herein, "depleting", with respect to cells expressing HER3, shall mean to lower the population of at least one type of cells that express or overexpress HER3 (e.g., HER3-positive cells in a solid tumor or circulating in a subject's blood).
According to certain aspects of this invention, a decrease is determined by comparison of the numbers of HER3-positive cells in the subject's blood or in a tissue biopsy, such as from the solid tumor, before and after initiation of treatment with the HER3 targeting agent. As such, and by way of example, a subject's HER3-positive cells may be considered to be depleted if the population is lowered, such as by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99%.
100801 -Inhibits growth" refers to a measurable decrease or delay in the growth of a malignant cell or tissue (e.g., tumor) in vitro or in vivo when contacted with a therapeutic or a combination of therapeutics or drugs, when compared to the decrease or delay in the growth of the same cells or tissue in the absence of the therapeutic or the combination of therapeutic drugs.
Inhibition of growth of a malignant cell or tissue in vitro or in vivo may be at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%.
[0081] The term "immune checkpoint therapy" refers to a molecule capable of modulating the function of an immune checkpoint protein in a positive or negative way in the furtherance of immune response against cancer cells. The term "immune checkpoint" refers to a protein directly or indirectly involved in an immune pathway that under normal physiological conditions acts to prevent uncontrolled immune reactions and thus for the maintenance of self-tolerance and/or tissue protection.
[00821 In the context of the present invention, an immune checkpoint therapy encompasses therapies such as antibodies capable of down-regulating at least partially the function of an inhibitory immune checkpoint (antagonist) and/or up-regulating at least partially the function of a stimulatory immune checkpoint (agonist). As example, an immune checkpoint therapy may refer to an antibody against an immune checkpoint inhibitor (ICI) that may be upregulated in certain cancers, and thus may inhibit the function of the ICI.
[0083] The term "DDRi" refers to an inhibitor of a DNA damage response pathway protein, of which a PARPi is an example. The term "PARPi" refers to an inhibitor of poly(ADP-ribose) polymerase. In the context of the present invention, the term PARPi encompasses molecules that may bind to and inhibitor the function of poly(ADP-ribose) polymerase, such as antibodies, peptides, or small molecules.
[00841 The term "CD47 blockade" refers to an agent that prevents CD47 binding to SIRPa, such as blocking agents that bind to either of CD47 or SIRPa, or those that modulate expression of CD47 or SIRPa, or those that otherwise inhibit the CD47/SIRPct axis. Without limitation, CD47 blockades encompass at least antibodies that bind to CD47 such as magrolimab, lemzoparlimab, and A0-176, SIRPa fusion proteins such as TTI-621 and TTI-622, agents that modulate the expression of CD47 and/or SIRPa, such as phosphorodiamidate morpholino oligomers (PMO) that block translation of CD47, and small molecule agents such as RRx -001.
100851 As used herein, administering to a subject one or more additional therapies, such as one or more of an immune checkpoint therapy and/or DDRi and/or CD47 blockade and/or radiosensitizer "in conjunction with" a HER3 targeting agent means administering the additional therapy before, during and/or after administration of the HER3 targeting agent. This administration includes, without limitation, the following scenarios: (i) the additional therapy is administered first, and the HER3 targeting agent is administered second; (ii) the additional therapy is administered concurrently with the HER3 targeting agent (e.g., the DDRi is administered orally once per day for n days, and the HER3 targeting agent is administered intravenously in a single dose on one of days 2 through n-1 of the DDRi regimen); (iii) the additional therapy is administered concurrently with the HER3 targeting agent (e.g., the DDRi is administered orally for a duration of greater than one month, such as orally once per day for 35 days, 42 days, 49 days, or a longer period during which the cancer being treated does not progress and during which the DDRi does not cause unacceptable toxicity, and the HER3 targeting agent is administered intravenously in a single dose on a day within the first month of the DDRi regimen); and (iv) the HER3 targeting agent is administered first (e.g., intravenously in a single dose or a plurality of doses over a period of weeks), and the additional therapy is administered second (e.g., the DDRi is administered orally once per day for 21 days, 28 days, 35 days, 42 days, 49 days, or a longer period during which the cancer being treated does not progress and during which the DDRi does not cause unacceptable toxicity).
Additional peimutations that would be obvious to one of skill in the art are possible and within the scope of the presently claimed invention.
[0086] An "article of manufacture" indicates a package containing materials useful for the treatment, prevention and/or diagnosis of the disorders described herein.
The article of manufacture may include a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc.
The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition which is by itself or combined with another composition effective for treating, preventing and/or diagnosing the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition may be a radi olab el ed HER3 targeting agent according to aspects of the presently disclosed invention.
100871 A "label" or "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and/or warnings concerning the use of such therapeutic products As used herein, a label may indicate that the composition is used for treating a HER3-positive cancer and may optionally indicate administration routes and/or methods. Moreover, the article of manufacture may include (a) a first container with a composition contained therein, wherein the composition includes FIER3 targeting agent; and (b) a second container with a composition contained therein, wherein the composition includes a further cytotoxic or otherwise therapeutic agent according to aspects of the presently disclosed invention. Alternatively, or additionally, the article of manufacture may further include a second (or third) container including a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
[0088] Throughout this application, various patents, patent applications and other publications are cited, each of which is hereby incorporated by reference in its entirety.
[0089] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing described herein, suitable methods and materials are described below.
[0090] EXPERIMENTAL RESULTS
[00911 An anti-HER3 IgG monoclonal antibody consisting of heavy chain SEQ ID
NO:77 and light chain SEQ ID NO:78 was prepared, conjugated to the chelator DOTA using p-SCN-Bn-DOTA and radiolabeled via chelation with Actinium-225 for further investigation as described below in connection with FIGS 3-11.
[00921 FIG. 3 shows ELISA assay binding characteristics of an Ac225 labeled DOTA-conjugated anti-HER3 monoclonal antibody ("HER3-ARC") versus the unmodified anti-HER3 antibody and a non-specific antibody (IgG), demonstrating that the modifications do not materially affect immune reactivity to HER3.
[0093] The binding properties of 225Ac-HER3-ARC were evaluated by ELISA. A 96 well plate was coated with human recombinant HER3 overnight following by incubation of serial dilutions (0 - 100 jig/m1) of anti-HER3, 225Ac-HER3-ARC and IgG
(immunoglobulin 1, nonpecific IgG1 control) for lh at room temperature. A secondary antibody (Goat Anti-human IgG F(ab')20-HRP) was added and incubated for 30 min on ice followed by color development using HC1 1M for 10 min. The sample absorbance was measured at 450nm. 225Ac-showed similar binding properties to those of the native antibody by ELISA
(HER3-ARC: ECso = 0.0017 lug/nil, HER3 EC50 = 0 0022 litg/m1).
[0094] FIG. 4 is a graph showing the results of flow cytometry assays examining the binding of the 225Ac-HER3-ARC, the unmodified anti-HER3 mAb, non-specific antibody control (IgG), and secondary antibody only control to HER3-positive NCI-H1975 cells (human lung adenocarcinoma, NSCLC) and BxPC-3 cells (human pancreatic adenocarcinoma).
[0095] The binding properties of 225Ac-HER3-ARC were evaluated by flow cytometry in HER3+ cells (NCI-H1975 and BxPC3). Solutions (100 gimp of anti-HER3, 225Ac-ARC and IgG (immunoglobulin 1, nonspecific IgG1) were added to HER+ cells and incubated for lh at room temperature. A PE labeled secondary antibody was added and incubated for 30 min on ice. Sample fluorescence was measured using a flow cytometer. The binding properties of 225Ac-HER3-ARC to fIER3+ positive cell lines resembled those of the unmodified anti-HER3 mAb.
[0096] FIG. 5 is a graph showing the in vitro cytotoxic effect of 225Ac-HER3-ARC to HER3-positive cell line NCI-H1975 as a function of radiation dose.
[00971 The cytotoxic effects of 225Ac-HER3-ARC to HER3+ cell line NCI-H1975 were evaluated in a colorimetric assay using CellTiter 96 AQueous Non-Radioactive Cell Proliferation Assay (MTS). NCI-H1975 cells were incubated with 225Ac-HER3-ARC
for 24h at 37 C. Unbound 225Ac-HER3-ARC was then removed, and cells were cultured for 72h at 37 C.
Absorbance at 490 nm was measured and % of cell viability calculated. 225Ac-showed potent in vitro cytotoxicity against HER3+ cell line NCI-H1975.
100981 FIG. 6A is a graph showing that 225Ac-FEER3-ARC upregulates cell surface calreticulin (CRT) in NCI-H1975 cells and FIG. 6B is a graph showing that 225Ac-HER3-ARC
upregulates CD47 on NCI-H1975 cells.
[0099] The effect of 225Ac-HER3-ARC on cell surface expression of calreticulin (CRT) and CD47 by HER3+ cell line NC1-H1975 was examined using flow cytometry. Cells were treated with 225Ac-HER3-ARC (100 nCi/m1) or PBS (control) for 72h. Following treatment, cells were stained for CRT and CD47. The results demonstrate that each of CRT
(FIG. 6A) and CD47 (FIG. 6B) is upregulated by 225Ac-HER3-ARC in NCI-H1975 cells.
[0100] FIG. 7A is a graph showing results of a phagocytosis assay demonstrating that the combination of 225Ac-HER3-ARC and an anti-CD47 blocking antibody enhanced phagocytosis of BxPC-3 cells versus either treatment alone. FIG. 7B is a graph showing results of a phagocytosis assay demonstrating that the combination of 225Ac-HER3-ARC and an anti-CD47 blocking antibody enhanced phagocytosis of NCI-H1975 cells versus either treatment alone.
The same key applies for FIGS. 7A and 7B.
[0101] The effect of combining 225Ac-HER3-ARC and anti-CD47 on phagocytosis in vitro was evaluated by flow cytometry. BxPC-3 (FIG. 7A) and NCI-H1975 (FIG.
7B) cells were seeded in 6-well plates 24hr prior to a 24hr incubation at 37 C with 225Ac-HER3-ARC.
Following 225Ac-HER3-ARC treatment, cells were cultured for 72hr at 37 C.
[0102] BxPC-3 and NCI-H1975 cells were stained with Vybrant DiD cell-labeling solution and treated with anti-human CD47 (Bio X Cell, Cat#BE0019) and mouse IgG1 isotype control (Bio X Cell, Cat#BE0083) for ihr at 37 C. Human macrophages were stained with Vybrant Di0 cell-labeling solution. Labeled human macrophages and target cells were cocultured for 2h at 37 C. Phagocytosis was assessed by evaluating the dual labeled cells (DiD+/Di0+).
[0103] FIG. 8 is graph showing the effects on tumor growth, in a human tumor (NCI-H1975 cell) mouse xenograft model, of a 225Ac-HER3-ARC at different radiation doses (100 nCi, 200 nCi, 400 nCi, 600 nCi) alone and at 200 nCi in combination with an anti-CD47 blocking antibody, of unlabeled anti-HER3 mAb, of anti-CD47 blocking antibody alone, and of vehicle-only control. Notably, tumor growth was almost entirely suppressed by 225Ac-HER-ARC at each of radiation doses 200 nCi, 400 nCi, 600 nCi and by the combination of 225Ac-HER-ARC (200 nCi) with the anti-CD47 mAb.
[0104] FIG. 9 is a graph showing body weight over time for the subjects of the experiment described in FIG. 8.
[0105] FIG. 10 is a graph showing the probability of survival over time for the experimental group subjects of the experiment described in FIG. 8.
[0106] Tumor xenograft studies examining the effect of HER2-ARC treatment alone and in combination with CD47 blockade on HER2-positive tumor growth were also performed.
Anti-HER2 mAb Trastuzumab was chemically conjugated to DOTA using p-SCN-Bn-DOTA
and labeled, via chelation, with either Actinium-225 or Lutetium-177 for use in these experiments.
[0107] FIG. 11 is a graph showing the comparative effects on tumor growth of vehicle only (control), magrolimab alone (10 mg/kg), 225Ac-trastuzumab alone (0.025 p.Ci/animal), and the combination of magrolimab (10 mg/kg) and 225Ac-trastuzumab (0.025 uCi/animal), in an NGS mouse xenograft model using the HER2-positive SK-0V3 human ovarian cancer cell line.
Each cohort consisted of eight animals.
[0108] FIG. 12 is a graph showing the comparative effects on tumor growth of vehicle only (control), magrolimab alone (10 mg/kg), 177Lu-trastuzumab alone (25 uCi/animal), and the combination of magrolimab (10 mg/kg) and 177Lu-trastuzumab (25 [Xi/animal), in an NGS
mouse xenograft model using the HER2-positive SK-0V3 human ovarian cancer cell line. Each cohort consisted of eight animals.
[0109] ASPECTS OF THE INVENTION
[0110] It is well documented in both preclinical and clinical studies that levels of HER3 can become downregulated following administration of a HER3 -targeting antibody (Mi shra, 2018). In preclini cal models with lumretuzumab, there was a dose-dependent (1-10mg/kg) downregulation of HER3 as measured by both immunohistochemistry and Western blotting (Maneses-Lorenta, 2015; Mirshberger, 2013) The lowest dose of lumretuzumab (0.3 mg/kg) did not result in IAER3 target downregulation (Maneses-Lorenta, 2015), and these low levels of lumretuzumab (0.1mg/kg and 0.3 mg/kg) were ineffective at controlling HER3-expressing tumors (Mirshberger, 2013). In clinical studies with lumretuzumab, downregulation of surface HER3 was observed in serial tumor biopsies in 92% of patients across all dose levels tested (100-2000mg; Meulendijks, 2016). Additionally, a decrease in total HER3 levels was observed in three out of five paired tumor biopsy samples in patients treated with the HER3-targeting antibody L.TM716 at 40 mg/kg (Reynolds, 2017).
[inn] While the internalization and degradation of HER3 may be beneficial to reduce phosphorylation of HER3 and subsequent signaling activity, reduction of surface levels of HER3 may impede antibody targeting of tumors. 'therefore, if repeat administration of a HER3-targeting antibody is desired or required for efficacy, the administration of a HER3-targeting antibody may result in downregulation of the target and preclude re-dosing.
The present inventors have found use of antibody radioconjugates (ARCs) circumvent the problems associated with the dose-dependent downregulation of HER3 as the lower antibody doses useful in therapeutic methods may not cause HER3 downregulation. Accordingly, the present inventors have found that HER3 targeting agents including a radioisotope are effective as diagnostic and therapeutic agents for improved tumor targeting and killing of HER3-expressing cancer cells, such as certain solid tumors. In particular, therapeutic methods that may include multiple doses of a HER3-targeting agent may provide improved tumor targeting and killing without causing a detrimental level of HER3 downregulation.
[0112] Thus, according to certain aspects of the presently disclosed invention, therapeutic methods for treating HER3-positive cancers using a radiolabeled HER3 targeting agent are provided. The methods may also include diagnostic steps to determine if and/or to what extent a patient has a HER3-positive cancer and/or the localization of such cancer, for example, by identifying and/or quantifying HER3 positive cells within solid tumors or circulating in a blood sample from the patient.
[0113] According to certain aspects, the therapeutic methods include administration of a radiolabeled HER3 targeting agent, such as a radiolabeled antibody, peptide, or small molecule that targets HER3, either alone or in combination with one or more additional therapeutic agents or modalities. According to certain aspects, the additional agent or modality may be any one or more of administration of an immune checkpoint therapy, a DDRi, a CD47 blockade, a chemotherapeutic agent, a small molecule oncology drug, external beam radiation, and brachytherapy.
[0114] According to certain aspects, the radiolabeled HER3 targeting agent may be administered to the patient in a patient specific composition in one or more doses.
[0115] According to certain aspects, the patient may be monitored at intervals during the therapy for the presence of HER3-positive cells to evaluate the reduction in HER3-positive cells.
Detecting a decreased number of the HER3-positive cells after treatment with the HER3 targeting agent, as compared to the number of HER3-positive cells prior to treatment may indicate effectiveness of the I-TER3 targeting agent in treating a HER3 -p o si ti ve cancer in the mammalian subject [0116] According to certain aspects, the method of treating cancer includes identifying a patient having a HER3-positive cancer by identifying HER3-positive cells and administering to the patient an effective amount of a HER3 targeting agent, either alone or in combination with an additional method of treatment. According to certain aspects, the additional method of treatment may be any one or more of administration of an immune checkpoint therapy, a DDRi, a CD47 blockade, a chemotherapeutic agent, a small molecule oncology drug, external beam radiation and brachy. therapy.
[0117] According to certain aspects, the chemotherapeutic agent is a radiosensitizer.
[0118] According to certain aspects, the radiolabeled HER3 targeting agent can be administered to a patient that has undergone, such as recently undergone a treatment, such as surgery for treatment of the cancer, such as to remove all or a portion of a solid tumor. Thus, for example, the radiolabeled 11-ER3 targeting agent may be administered perioperatively or post-operatively.
[0119] HER3 targeting agents [0120] An object of the presently disclosed invention is to provide radiolabeled HER3-, such as human HER3-, targeting agents for diagnostic use and/or for therapeutic use, such as in the diagnosis and/or treatment of HER3-positive cancers. Radiolabeled HER3 -targeting agents can effect a therapeutic response via the delivery of DNA-damaging ionizing radiation to cells, for example, alpha-particles that induce double strand DNA breaks and cell death.
[0121] Exemplary anti-HER3 antibodies (also referred to as "HER3 antibodies"
herein) , such as anti-human HER3 antibodies, that that may be radiolabeled and embodied in and/or used in the various aspect of the presently disclosed invention include, without limitation, the following antibodies, and antibodies such as but not limited to immunoglobulins, such as but not limited to IgG, that (i) include the heavy chain variable region of the HER3 antibody or heavy chain, (ii) include 1, 2 or 3 of the heavy chain CDRs (e.g., by the Kabat definition) of the HER3 antibody or heavy chain or those recited, (iii) include the light chain variable region of the HER3 antibody or light chain, and/or (iv) include 1, 2 or 3 of the light chain CDRs (e.g., by the Kabat definition) of the HER3 antibody or light chain or those recited. It should also be understood that where a HER3 antibody heavy chain or HER3 antibody light chain is disclosed that includes an N-terminal leader sequence, also intended to be disclosed for embodiment in and use in the various aspects of the invention are corresponding heavy chains and corresponding light chains that lack the leader sequence.
[0122] An exemplary HER3 antibody that may be radiolabeled and embodied in and/or used inthe presently disclosed invention may, for example, include a murine monoclonal antibody against HER3 including a heavy chain having the amino acid sequence as set forth in SEQ ID NO.9 or 11 and/or a light chain having the amino acid sequence as set forth in SEQ ID
NO:10 or 12, or an antibody such as a humanized antibody derived from one or more of said sequences. An exemplary HER3 antibody that may be radiolabeled and embodied in and/or used in the presently disclosed invention may include or a heavy chain with an N-terminal region having the sequence set forth in SEQ ID NO:13 and/or a light chain with an N-terminal region having the sequence as set forth in SEQ ID NO:14. A HER3 antibody that may be similarly embodied or used in various aspect of the invention may, for example, include the heavy chain variable region having the amino acid sequence as set forth in SEQ ID NO:7, and/or a light chain variable region having an amino acid sequence as set forth in SEQ ID NO:8;
and/or a heavy chain including one or more of CDR1, CDR2 and CDR3 having the amino acid sequences respectively set forth in SEQ ID NOS:1-3, and/or a light chain with one or more of the CDR1, CD2 and CDR3 having the amino acid sequences respectively set forth in SEQ ID
NOS:4-6. See FIGS. 1 and 2 for a further description of these sequences. A HER3 antibody embodied in and/or used in any of the aspects of the invention may, for example, include any combination of the aforementioned light chain sequences and/or heavy chain sequences.
[0123] An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including a CDR-H1 including SEQ ID NO:15, a CDR-H2 including SEQ ID
NO:16, and a CDR-H3 including SEQ ID NO: 17, and/or an immunoglobulin light chain variable region including a CDR-L1 including SEQ ID NO:18, a CDR-L2 including SEQ lD NO:19, and a CDR-L3 including SEQ ID NO:20. An exemplary An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including SEQ ID NO:21 and/or an immunoglobulin light chain variable region including SEQ ID NO:22. An exemplary HER3 antibody includes an immunoglobulin heavy chain amino acid sequence of SEQ ID
NO:23 and/or an immunoglobulin light chain amino acid sequence of SEQ ID NO:24.
[0124] An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including a CDR-H1 including SEQ ID NO:25, a CDR-H2 including SEQ ID
NO:26, and a CDR-H3 including SEQ ID NO:27; and/or an immunoglobulin light chain variable region including a CDR-L1 including SEQ ID NO:28, a CDR-L2 including SEQ lD NO:29, and a CDR-L3 including SEQ ID NO:30. An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including SEQ ID NO:31 and/or an immunoglobulin light chain variable region including SEQ ID NO:32.. An exemplary HER3 antibody includes an immunoglobulin heavy chain amino acid sequence of SEQ ID NO:33 and/or an immunoglobulin light chain amino acid sequence of SEQ ID NO:34 [0125] An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including a CDR-H1 including SEQ ID NO:35, a CDR-H2 including SEQ ID
NO:36, and a CDR-H3 including SEQ ID NO:37; and/or an immunoglobulin light chain variable region including a CDR-L1 including SEQ ID NO:38, a CDR-L2 including SEQ ID NO:39, and a CDR-L3 including SEQ ID NO:40. An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including SEQ ID NO:41, and/or an immunoglobulin light chain variable region SEQ ID NO:42. An exemplary HER3 antibody includes an immunoglobulin heavy chain amino acid sequence of SEQ ID NO:43 and an immunoglobulin light chain amino acid sequence of SEQ ID NO:44.
[0126] An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including a CDR-H1 including SEQ ID NO:45, a CDR-H2 including SEQ ID
NO:46, and a CDR-H3 including SEQ ID NO:47; and/or an immunoglobulin light chain variable region including a CDR-L1 including SEQ ID NO:48, a CDR-L2 including SEQ ID NO:29, and a CDR-L3 including SEQ ID NO:49. An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including SEQ ID NO:50 and/or an immunoglobulin light chain variable region including SEQ ID NO:51. An exemplary HER3 antibody includes an immunoglobulin heavy chain amino acid sequence of SEQ ID NO:52 and/or an immunoglobulin light chain amino acid sequence of SEQ ID NO:53.
[01271 An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including a CDR-H1 including SEQ ID NO:54, a CDR-H2 including SEQ ID
NO:55, and a CDR-H3 including SEQ ID NO:56; and/or an immunoglobulin light chain variable region including a CDR-L1 including SEQ ID NO:28, a CDR-L2 including SEQ ID NO:29, and a CDR-L3 including SEQ ID NO:30. An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including SEQ ID NO:57 and/or an immunoglobulin light chain variable region including SEQ ID NO:58. An exemplary HER3 antibody includes an immunoglobulin heavy chain amino acid sequence of SEQ ID NO:59 and/or an immunoglobulin light chain amino acid sequence of SEQ ID NO: 60.
[0128] An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including a CDR-H1 including SEQ ID NO:61, a CDR-H2 including SEQ ID
NO:62, and a CDR-H3 including SEQ ID NO:63; and/or an immunoglobulin light chain variable region including a CDR-L1 including SEQ ID NO:64, a CDR-L2 including SEQ ID NO:65, and a CDR-L3 including SEQ ID NO:66. An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including SEQ ID NO:67, and/or an immunoglobulin light chain variable region including SEQ ID NO:68. An exemplary HER3 antibody includes an immunoglobulin heavy chain amino acid sequence of SEQ ID NO:69 and an immunoglobulin light chain amino acid sequence of SEQ ID NO:70.
[0129] An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including a CDR-H1 including SEQ ID NO:71, a CDR-H2 including SEQ ID
NO:72, and a CDR-H3 including SEQ ID NO:66; and/or an immunoglobulin light chain variable region including a CDR-L1 including SEQ ID NO:28, a CDR-L2 including SEQ ID NO:29, and a CDR-L3 including SEQ ID NO:30. An exemplary HER3 antibody includes an immunoglobulin heavy chain variable region including SEQ ID NO:73, and/or an immunoglobulin light chain variable region including SEQ ID NO:74. An exemplary HER3 antibody includes an immunoglobulin heavy chain amino acid sequence of SEQ ID NO.75 and/or an immunoglobulin light chain amino acid sequence of SEQ ID NO:76.
[0130] An exemplary HER3 antibody includes an immunoglobulin heavy chain amino acid sequence of SEQ ID NO:77 and/or an immunoglobulin light chain amino acid sequence of SEQ ID NO.78.
[0131] An exemplary HER3 antibody includes an immunoglobulin light chain variable region including SEQ ID NOS:86, 87, 88, 89, 90 or 91 and/or a heavy chain variable region including SEQ ID NOS:79, 80, 81, 82, 83, 84 or 85.
[01321 An exemplary HER3 antibody includes an immunoglobulin heavy chain sequence including SEQ ID NO:92, 94, 95, 98 or 99 and/or an immunoglobulin light chain sequence including SEQ ID NO:93, 96, 97, 100 or 101.
[0133] Exemplary HER3 antibodies also include Barecetamab (ISU104) from Isu Abxis Co and any of the HER3 antibodies disclosed in U.S. Patent No. 10,413,607.
[01341 Exemplary HER3 antibodies also include HIMBD-001 (10D1F) from Hummingbird Bioscience Pte. and any of the HER3 antibodies disclosed in International Pub.
Nos. WO 2019185164 and W02019185878, U.S. Patent 10,662,241; and U.S. Pub.
Nos.
20190300624, 20210024651, and 20200308275.
[01351 Exemplary HER3 antibodies also include the HER2/HER3 bispecific antibody MCLA-128 (i.e., Zenocutuzumab) from Merus N.V.; and any of the HER3 antibodies, whether monospecific or multi-specific, disclosed in U.S. Pub. Nos. 20210206875, 20210155698, 20200102393, 20170058035, and 20170037145.
[0136] Exemplary HER3 antibodies also include the HER3 antibody Patritumab (U3-1287), an antibody including heavy chain sequence SEQ ID NO:106 and/or light chain sequence SEQ ID NO:7 which are reported chains of Patritumab, and any of the HER3 antibodies disclosed in U.S. Patent Nos. 9,249,230 and 7,705,130 and International Pub.
No.
W02007077028.
[01371 Exemplary HER3 antibodies also include the HER3 antibody MM-121 and any of the HER3 antibodies disclosed in U.S. Patent No. 7,846,440 and International Pub. No.
W02008100624.Exemplary HER3 antibodies also include the EGER/HER3 bispecific antibody DL1 and any of the HER3 antibodies, whether monospecific or multi-specific, disclosed in U.S.
Patent Nos. 9,327,035 and 8,597,652, U.S. Pub. No. 20140193414, and International Pub. No.
W02010108127.
[0138] Exemplary HER3 antibodies also include the HER2/HER3 bispecific antibody MM-111 and any of the HER3 antibodies, whether monospecific or multi-specific, disclosed in U.S. Pub. Nos. 20130183311 and 20090246206 and International Pub. Nos.
W02006091209 and W02005117973.
[0139] According to certain aspects, the HER3 targeting agent includes an anti-antibody that binds to an epitope of HER3 recognized by Patritumab from Daiichi Sankyo, Seribantumab (MM-121) from Merrimack Pharmaceuticals, Lumretuzumab from Roche, Elgemtumab from Novartis, GSK2849330 from GlaxoSmitliKline, CDX-3379 of Celldex Therapeutics, EV20 and MP-RM-1 from MediPharma, Barecetamab (1SU104) from lsu Abxis Co., HMBD-001 (10D1F) from Hummingbird Bioscience Pte., REGN1400 from Regeneron Pharmaceuticals, and/or AV-203 from AVEC/ Oncology. According to certain aspects, the anti-HER3 antibody is selected from one or more of Patritumab, Seribantumab or an antibody including heavy chain sequence SEQ ID NO:108 and/or light chain sequence SEQ
ID NO:109 which are reported for Seribantumab, Lumretuzumab or an antibody including heavy chain sequence SEQ ID NO:110 and/or light chain sequence SEQ ID NO:111 which are reported for Lumretuzumab, Elgemtumab or an antibody including heavy chain sequence SEQ ID
NO:112 and/or light chain sequence SEQ ID NO:113 which are reported for Elgemtumab, AV-203, CDX-3379, GSK2849330, EV20, MP-RM-1, ISU104, HMBD-001 (10D1F), and REGN1400.
Exemplary antibodies along with exemplary treatment indications are also described in Table 1.
Table 1 Company Name Product Name Targets Therapeuti Exemplary Indications (Originator) c Modality Aveo Pharmaceuticals CAN017, AV-203 HER3 Antibody Esophageal cancer, solid Inc. tumors Celldex Therapeutics CDX-3379, HER3 Antibody Head and neck cancer, solid Inc. ktn3379 tumors Daiichi Sankyo Co. patritumab HER3 Antibody Non-small cell lung cancer Ltd. (AMG 888, U3- (NSCLC), breast cancer, head 1287) and neck cancer Daiichi Sankyo Co. U3-1402 HER3 Antibody- NSCLC, breast cancer, colon Ltd. drug cancer conjugate GSK GSK2849330 HER3 Antibody Solid tumors Hummingbird HMBD-001 HER3 Antibody Gastric cancer Bioscience Pte. Ltd. (10D1F) Isu Abxis Co. Ltd. ISU104 HER3 Antibody Cancer (unspecified) MediPharma MP-R_M-1 HER3 Antibody Solid tumors MediPhanna EV20 HER3 Antibody Solid tumors Merrimack Se ribantumab HER3 Antibody NSCLC, breast cancer, Pharmaceuticals Inc. (MM-121, ovarian cancer SAR256212) Novartis AG elgem tumab HER3 Antibody Esophageal cancer, Breast (LJM716) cancer, solid tumors R_egeneron REGN1400 HER3 Antibody Cancer (unspecified) Pharmaceuticals Inc.
Roche Lumretuzumab HER3 Antibody Breast cancer, solid tumors (RG7116 or R05479599) [0140] It should be understood that wherever in this disclosure specific antibodies, specific antibody heavy chains and specific antibody light chains are disclosed, against HER3 or against any target, also intended to be disclosed for embodiment in or use in the various aspects of the invention are antibodies, such as but not limited to immunoglobulins, such as but not limited to IgG, that (i) include the heavy chain variable region of the disclosed antibody or heavy chain, (ii) include 1, 2 or 3 of the heavy chain CDRs (e.g., by Kabat definition) of the disclosed antibody or heavy chain, (iii) include the light chain variable region of the disclosed antibody or light chain, and/or (iv) include 1, 2 or 3 of the light chain CDRs (e.g., by Kabat definition) of the disclosed antibody or light chain. It should also be understood that wherever in this disclosure an antibody heavy chain or an antibody light chain is disclosed that includes an N-terminal leader sequence, also intended to be disclosed for embodiment in and use in the various aspects of the invention are corresponding heavy chains and corresponding light chains that lack the leader sequence [0141] Further, the invention provides modified versions of any of the recited amino acid sequences in which one or more isomeric amino acid replacements with exact mass, such as Leu for Ile or vice versa, are made (in, e.g., any of SEQ ID NOS:1-14 listed in FIG. 1 and 2).
Additionally, certain portions of these sequences may be substituted, such as by related portions from human immunoglobulins to form chimeric immunoglobulins (i.e., chimeric or humanized HER3). Exemplary substitutions include all or portions of the human leader sequence, and/or the conserved regions from human IgGl, IgG2, or IgG4 heavy chains and/or human Kappa light chain.
[0142] The sequence and structure of human HER3, human HER2, and human EGER
(HER1) are all known. An amino acid sequence of the human HER3 precursor protein (receptor tyrosine-protein kinase erbB-3 isoform 1 precursor NCBI Reference Sequence: NP
001973.2) is provided herein as SEQ ID NO.115. Those skilled in the art will readily appreciate that given known target protein amino acid sequences, various types of suitable antibodies and antibody mimetics specific for the extracellular domain of HER3, such as of human HER3, for use in the various aspects of the invention, may be produced using immunization and/or panning and/or antibody engineering techniques that are well established in the art.
[0143] A HER3 targeting agent that is radiolabeled for use in the various embodiments of the invention may, for example, include a HER3 binding peptide such as chelator-bearing HER3 binding peptide, such as a DOTA-bearing HER3 binding peptide, such as any of those disclosed in U.S. Pub. No. 20200121814.
[0144] According to certain aspects, the HER3 targeting agent includes/is a multi-specific targeting agent, such as a multi-specific antibody, against a first epitope of HER3 and at least a second epitope of HER3, or against HER3 and one or more different antigens such as one or more of EGFR (HERO, HER2, TROP2, and T-cell receptor gamma (TCRy) chain alternate reading frame protein (TRAP). Exemplary multi-specific antibodies that may be used include bispecific antibodies against HER3/HER2 such as MM-111 from Merrimack Pharmaceuticals or MCL A-128 (i.e., Zenocutuzumab) from Merus N.V.; or against IGF-1R/HER3 such as MM-141 (i.e., Istiratumab) from Merrimack Pharmaceuticals; or against EGFR/HER3 such as MEHD7945A (i.e., Duligotumab) from Roche or any of the cetuximab-based bispecific or multi-specific zybodies from Zyngenia Inc.
[0145] According to certain aspects, a composition including a mixture of a targeting agent, such as an antibody against HER3, and one or more antibodies against one or more different antigens, in which one or more of the antibodies is radiolabeled, is provided and/or used. An exemplary antibody composition including an antibody mixture includes at least Sym013 from Symphogen having six monoclonal antibodies against EGFR (HERO, HER2, and IIER3. In one aspect of the invention, one or more of the antibodies, such as an anti-HER3 antibody, of Sym013 may be radiolabeled. A related aspect of the invention provides a composition including targeting agents against EGFR (HER1), HER2, ad HER3, such as antibodies, in which one or more in any combination or all are radiolabeled [0146] The present invention further provides multi-specific targeting agents, compositions and related methods of treating a proliferative disease or disorder which include administration of (i) a multi-specific antibody against two or more epitopes of HER3, or against an epitope of HER3 and an epitope of one or more additional different antigens, and/or (ii) administration of a HER3 targeting agent such as an antibody and one or more discrete targeting agents directed against one or more cancer associated antigens wherein one or more of the targeting agents, such as the HER3 targeting agent is radiolabeled. The additional different antigens may, for example, be antigens whose expression is upregulated on cells involved in various diseases or disorders, such as proliferative disorders, for example, solid tumor cancers, such as those in which HER3 is also or can also be upregulated. For example, the additional different antigens may be selected from the group including mesothelin, TSHR, CD19, CD123, CD22, CD30, CD45, CD171, CD138, CS-1, CLL- 1, GD2, GD3, B-cell maturation antigen (BCMA), Tn Ag, prostate specific membrane antigen (PSMA), ROR1, FLT3, TROP2, T-cell receptor gamma (TCRy) chain alternate reading frame protein (TRAP), fibroblast activation protein (FAP), calreticulin, phosphatidylserine, GRP78 (BiP), TAG72, CD38, CD44v6, CEA, EPCAM, B7H3, KIT, IL-13Ra2, interleukin-11 receptor a (IL-11Ra), PSCA, PRS
S21, VEGFR2, LewisY, CD24, platelet-derived growth factor receptor-beta (PDGFR-beta), SSEA-4, CD20, Folate receptor alpha (FRa), ERBB2 (Her2/neu), MUC1, epidermal growth factor receptor (EGFR), EGFRvIII, NCAM, Prostase, PAP, ELF2M, Ephrin B2, IGF-I receptor, CAIX, LMP2, gp100, bcr-abl, tyrosinase, EphA2, Fucosyl GM1, sLe, GM3, DR5, 5T4, TGS5, HMWMAA, o-acetyl-GD2, Folate receptor beta, TEM1/CD248, TEM7R, CLDN6, GPRC5D, CXORF61, CD97, CD 179a, ALK, Polysialic acid, PLAC1, GloboH, UPK2, HAVCR1, ADRB3, PANX3, GPR20, LY6K, 0R51E2, TARP, WT1, NY-ES0-1, LAGE-la, MAGE-Al, legumain, HPV E6,E7, MAGE Al, MAGEA3, MAGEA3/A6, ETV6-,AML, sperm protein 17, XAGE1, Tie 2, MAD-CT-1, MAD-CT-2, Fos-related antigen 1, prostein, survivin and telomerase, PCTA-1/Galectin 8, KRAS, MelanA/MART1, Ras mutant, hTERT, sarcoma translocation breakpoints, ML-IAP, ERG (TMPRSS2 ETS fusion gene), NA17, PAX3, Androgen receptor, Cyclin B
1, MYCN, RhoC, TRP-2, CYP1B 1, BORIS, SART3, PAX5, OY- TES 1, LCK, AKAP-4, SSX2, RAGE-1, human telomerase reverse transcriptase, RU1, RU2, intestinal carboxyl esterase, mut hsp70-2, CD79a, CD79b, CD72, LAIR', FCAR, L11LRA2, CD300LF, CLEC12A, BST2, EMR2, LY75, GPC3, FCRL5, GPA7, and IGLLI.
[0003] Exemplary DRS (death receptor 5) targeting agents that may be radiolabeled, unlabeled or drug-conjugated for use in the invention include the monoclonal anti-DR5 antibodies m apatumum ab, c on atumum ab, lex atum um ab, tigatuzumab, drozitumab, and LB Y-135. Such DR5 targeting agents may, for example, be used in combination with a radiolabeled TIER3 targeting agents for the treatment of ovarian, breast, cervical prostate, gastric, bladder, lung, melanoma, colorectal and squamous cell carcinoma cancers and any of the cancers disclosed herein.
[0004] Exemplary 5T4 (Trophoblast glycoprotein (TBPG)) targeting agents that may be radiolabeled, drug-conjugated, or unlabeled for use in the invention include the anti-5T4 monoclonal antibodies MED10641, ALG.APV-527, Tb535, H6-DM5, and ZV0508, as well as Naptumomab estafenatox or the Fab portion thereof. Such 5T4 targeting agents may, for example, be used in combination with a radiolabeled HER3 targeting agent for the treatment of ovarian, head and neck, breast, prostate, gastric, bladder, lung, melanoma, colorectal and squamous cell carcinoma cancers and any of the cancers disclosed herein.
[0005] Exemplary HER2 (ERBB2) targeting agents that may be radiolabeled, drug-conjugated, or unlabeled for use in the invention include the monoclonal antibodies trastuzumab and pertuzumab. Applicants have successfully conjugated Trastuzumab with p-SCN-DOTA and radiolabeled the composition with 225Ac or 177Lu.. Exemplary ADCs targeting HER2 that may be used include fam-trastuzumab deruxtecan-nxki (Enhertug; AstraZeneca/Daiichi Sankyo) and Trastuzumab emtansine (Roche/Genentech). The anti-HER2 antibody may, for example, also be a multi-specific antibody, such as bispecific antibody, against any available epitope of 1-1ER3/1-IER2 such as MNI- 1 I 1 and MM-141/Istiratumab from Merrimack Pharmaceuticals, MCLA-128 from Merus NV, and MEEID7945A/Duligotumab from Genentech. HER2 targeting agents may, for example, be used in combination with a radiolabeled HER3 targeting agent in the treatment of HER2-expressing cancers such as ovarian, breast, metastatic breast, esophageal, lung, cervical, and endometrial cancers including but not limited to those that are both HER2-and HER3 -positive.
[0131:161 The amino acid sequences of the heavy chain and the light chain of Trastuzumab reported by DrugBank Online are: heavy chain (SEQ ID NO:102) and light chain (SEQ ID
NO:103) and a HER2 binding antibody including one or both of said chains may be embodied in or used in the various embodiments of the invention.
[0007] The amino acid sequences of the heavy chain and the light chain of Pertuzumab reported by DrugBank Online are: heavy chain (SEQ ID NO:104) and light chain (SEQ ID
NO:105) and a HER2 binding antibody including one or both of said chains may be embodied in or used in the various embodiments of the invention.
[0008] Exemplary CD33 targeting agents that may be radiolabeled, drug-conjugated, or unlabeled for use in the invention include the monoclonal antibodies lintuzumab, gemtuzumab, and vadastuximab. In combination with a radiolabeled HER3 targeting agent as disclosed herein, a CD33 targeting therapeutic agent may, for example, be used to treat solid cancers, such as ovarian, breast, cervical prostate, gastric, bladder, lung, melanoma, colorectal and squamous cell carcinoma cancers and any of the cancers disclosed herein, for example, by depleting myeloid-derived suppressor cells (MDSCs). In one aspect, the CD33 targeting agent used in combination with a radiolabeled 1-IER3 targeting agent is 225Ac-lintuzumab. In another aspect, the CD33 targeting agent used in combination with a radiolabeled HER3 targeting agent is the ADC gemtuzumab ozogamicin (MylotargR; Pfizer).
[0009] Exemplary CD38 targeting agents that may be radiolabeled, drug-conjugated, or unlabeled for use in the invention include anti-CD38 monoclonal antibodies such as daratumumab (Darzalexa); Johnson and Johnson) and isatuximab (Sarclisag;
Sanofi) or antigen-binding fragments thereof. Such CD38 targeting agents may, for example, be used in combination with the radiolabeled HER3 targeting agents in the treatment of solid tumors that may, for example, be infiltrated with CD38-positive suppressive immune cells, such as but not limited to ovarian, breast, cervical prostate, gastric, bladder, lung, melanoma, colorectal and squamous cell carcinoma cancers and any of the cancers disclosed herein.
[00101 Exemplary different antigens (over HER3) that may be targeted by a multi-specific antibody according to aspects of the present invention include at least HER1 (EGFR), HER2, and IGF-1R. Exemplary HER3 multi-specific targeting agents include multi-specific antibodies such as MM-111 from Merrimack Pharmaceuticals or MCLA-128 (i.e., Zenocutuzumab) from Merus N.V.; or against IGF-1R/HER3 such as MM-141 (i.e., Istiratumab) from Merrimack Pharmaceuticals; or against EGFR/HER3 such as MEHD7945A (i.e., Duligotumab) from Roche, the cetuximab-based bispecific zybody from Zyngenia Inc., and the multi-specific antibody composition Sym-013 from Symphogen. See also Table 2 for further description and exemplary indications.
Company Product Name Targets Therapeutic Exemplary Name Modality Indications (Originator) Merrimack Istiratumab (MM- IGF-1R;HER3 Bispecific Antibody Solid tumors Pharmaceuticals 141) Inc.
Merrimack MM-111 HER2;HER3 Bispecific Antibody Breast cancer, solid Pharmaceuticals tumors Inc.
Merus N.V. MCLA-128 HER2;HER3 Bispecific Antibody NSCLC, breast cancer, ovarian cancer, colorectal cancer, gastric cancer, endometrial cancer, solid tumors Roche Duligotuzmab EGFR;HER3 Antibody Colorectal cancer, (MEHD7945A, epithelial cancer, RG7597) head and neck cancer, solid tumors Symphogen Sym013 HER1, HER2, Antibody (mixture) Solid tumors Zyngenia Inc. Cetuximab-based EGFR;I IER3 Antibody Cancer (unspecified) bispecific zybody [01471 The present invention also provides methods of treating a proliferative disease or disorder that includes administration of a first antibody against at least one epitope of HER3, and administration of a second antibody, wherein the second antibody is against a different epitope of HER3 than the first antibody, or is against an epitope of a different antigen, such as one or more antigens selected from the list of different antigens presented above. One or more of the HER3 antibodies may be radiolabeled. Antibodies against the different antigens may, for example, also be radiolabeled in any combination.
[0148] Such combinations, presented as a multi-specific antibody or more than one monoclonal antibody as indicated above, may deliver a synergistic therapeutic effect comparable to the effectiveness of a monotherapy with only an antibody against HER3, while reducing adverse side effects of the monotherapy. Moreover, the combination may deliver an improved effectiveness over the monotherapy, which may, for example, be measured by reduction in the total tumor cell number, increase in the length of time to relapse, and other indicia of patient health.
[0149] When the methods include administration of a multi-specific antibody, the first target recognition component may, for example, include one of: a first full-length heavy chain and a first full-length light chain, a first Fab fragment, a first single-chain variable fragment (scFvs), or other type of antibody. The second target recognition component may, for example, include one of: a second full length heavy chain and a second full length light chain, a second Fab fragment, or a second single-chain variable fragment (scFvs) or other type of antibody.
Moreover, the second target recognition component may be derived from a different epitope of the HER3 antigen or may be derived from any of the antigens listed above [0150] A HER3 targeting agent may include a radioisotope, and any additional antibodies against other antigens may optionally include a radioisotope. According to certain aspects of the present invention, when the immunotherapy includes a bispecific antibody, either one or both of the first target recognition component and the second target recognition component, or any part of the hi specific targeting agent, may include a radioisotope.
[0151] According to certain aspects of the present invention, the radiolabeled targeting agent may exhibit essentially the same immunoreactivity to the antigen as a control targeting agent, wherein the control targeting agent includes the naked targeting agent or otherwise unlabeled targeting agent against the same epitope of the antigen (i.e., HER3) as the radiolabeled targeting agent.
[0152] According to certain aspects of the present invention, the targeting agent may be labeled with 225Ac, and may be at least 5-fold more effective at causing cell death of HER3-positive cells than a control monoclonal antibody, wherein the control monoclonal antibody includes a naked or unlabeled antibody against the same epitope of the antigen as the 225Ac labeled antibody. For example, a 22'Ac labeled monoclonal antibody may be at least 10-fold more effective, at least 20-fold more effective, at least 50-fold more effective, or at least 100-fold more effective at causing cell death of HER3-positive cells than the control monoclonal antibody.
[0153] According to certain aspects of the present invention, the methods may include administration of labeled and unlabeled (e.g., "naked") fractions of the HER3 targeting agent, such as an antibody, antibody fragment, etc. For example, the un-labeled fraction may include the same antibody against the same epitope as the labeled fraction. In this way, the total radioactivity of the antibody may be varied or may be held constant while the overall antibody protein concentration may be held constant or may be varied, respectively. For example, the total protein concentration of un-labeled antibody fraction administered may vary depending on the exact nature of the disease to be treated, age and weight of the patient, identity of the monoclonal antibody, and the label (e.g., radionuclide) selected for labeling of the monoclonal antibody.
[0154] According to certain aspects of the present invention, the effective amount of the anti-HER3 antibody is a maximum tolerated dose (MTD) of the anti-HER3 antibody.
[0155] According to certain method aspects of the present invention, when more than one antibody is administered, the antibodies may be administered at the same time.
As such, according to certain aspects of the present invention, the antibodies may be provided in a single composition. Alternatively, the two antibodies may be administered sequentially. As such, the radiolabeled IfER3 targeting agent may be administered before the second antibody, after the second antibody, or both before and after the second antibody. Moreover, the second antibody may be administered before the radiolabeled HER3 targeting agent, after the radiolabeled HER3 targeting agent, or both before and after the radiolabeled HER3 targeting agent.
[0156] According to certain aspects of the methods of the present invention, a radiolabeled HER3 targeting agent may be administered according to a dosing schedule selected from the group consisting of one every 7, 10, 12, 14, 20, 24, 28, 35, and 42 days throughout a treatment period, wherein the treatment period includes at least two doses.
[0157] According to certain aspects of the present invention, the radiolabeled targeting agent may be administered according to a dose schedule that includes 2 doses, such as on days 1 and 5, 6, 7, 8, 9, or 10 of a treatment period, or days 1 and 8 of a treatment period.
[0158] Administration of the radiolabeled HER3 targeting agents of the present invention, in addition to other therapeutic agents, may be provided in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated.
Administration may be intratracheal, intranasal, epidermal and transdermal, oral or parenteral.
Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration In some embodiments a slow-release preparation including the targeting agents(s) and/or other therapeutic agents may be administered. The various agents may be administered as a single treatment or in a series of treatments that continue as needed and for a duration of time that causes one or more symptoms of the cancer to be reduced or ameliorated, or that achieves another desired effect.
[0159] The dose(s) may vary, for example, depending upon the identity, size, and condition of the subject, further depending upon the route by which the composition is to be administered and the desired effect. Appropriate doses of a therapeutic agent depend upon the potency with respect to the expression or activity to be modulated. The therapeutic agents can be administered to an animal (e.g., a human) at a relatively low dose at first, with the dose subsequently increased until an appropriate response is obtained.
[0160] The radiolabeled HER3 targeting agent may be administered simultaneously or sequentially with the one or more additional therapeutic agents. Moreover, when more than one additional therapeutic agent is included, the additional therapeutic agents may be administered simultaneously or sequentially with each other and/or with the radiolabeled HER3 targeting agent.
[0161] Radiolabeling the HER3 targeting agent [0162] The HER3 targeting agent and other targeting agents disclosed herein may, for example, be labeled with a radioisotope, such as a beta emitter (e.g. 177Lu) or an alpha emitter (e.g., 225Ac), through conjugation of a chelator molecule, and chelation of the radioisotope thereto. According to certain aspects, the targeting agent may be an antibody against that is deglycosylated in the constant region, such as at asparagine-297 (Asn-297, N297; Kabat number) in the heavy chain CH2 domain, for the purpose of uncovering a unique conjugation site, glutamine (i.e., Gln-295, Q295) so that it is available for conjugation with bifunctional chelator molecules.
[0163] According to certain aspects, the radiotherapeutic may be an antibody that may have reduced disulfide bonds such as by using reducing agents, which may then be converted to dehydroalanine for the purpose of conjugating with a bifunctional chelator molecule.
[0164] According to certain aspects, the radiotherapeutic may be an antibody for which the disulfide bonds have been reduced using reducing agents, which is then conjugated via aryl bridges with a bifunctional chelator molecule. For example, according to certain aspects a linker molecule such as 3,5-bis(bromomethyl)benzene may be used to bridge the free sulfhydryl groups on the antibody.
[0165] According to certain aspects, the radiotherapeutic may be an antibody that may have certain specific existing amino acids replaced with cysteine(s) that then can be used for site-specific labeling.
Exemplary chelators that may be linked to targeting agents in the various aspects of the invention include: 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) or a derivative thereof; 1,4,7-triazacyclononane-1,4-diacetic acid (NODA) or a derivative thereof; 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) or a derivative thereof;
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or a derivative thereof; 1,4,7-triazacyclononane, 1-glutaric acid-4,7-diacetic acid (NODAGA) or a derivative thereof; 1,4,7,10-tetraazacyclodecane, 1-glutaric acid-4,7,10-triacetic acid (DOTAGA) or a derivative thereof;
1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) or a derivative thereof;
1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-di acetic acid (CB-TE2A) or a derivative thereof;
diethylene triamine pentaacetic acid (DTPA), its diester, or a derivative thereof, 2-cyclohexyl diethylene triamine pentaacetic acid (CHX-A"-DTPA) or a derivative thereoff, deforoxamine (DFO) or a derivative thereof, 1,2[[6-carboxypyridin-2-yl]methylamino]ethane (1-12dedpa) or a derivative thereof; DADA or a derivative thereof; 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic acid) (DOTP) or a derivative thereof, 4-amino-6-[[16-[(6-carboxypyridin-2-yl)methyl]-1,4,10,13-tetraoxa-7,16-diazacyclooctadec-7-ylimethylThyridine-2-carboxylic acid (VIACROPA-NI-12) or a derivative thereof; MACROPA or a derivative thereof;
1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (TCMC) or a derivative thereof, { 4- [2-(bi s-carboxymethylamino)-ethyl]-7-carb oxym ethyl-[1,4, 7]tri azonan-l-y1}-aceti c acid (NETA) or a derivative thereof, Diamsar or a derivative thereof, 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid (TRAP, PRP9, TRAP-Pr) or a derivative thereof; N,N'-bis(6-carboxy-2-pyridylmethyl)ethylenediamine-N,N'-diacetic acid (H4octapa) or a derivative thereof; N,N'41-benzy1-1,2,3-triazole-4-ylimethyl-N,N'46-(carboxy)pyridin-2-y1]-1,2-diaminoethane (H2azapa) or a derivative thereof; N,N"-[[6-(carboxy)pyridin-yl]methyl]diethylenetriamine-N,N,N"-triacetic acid (H5decapa) or a derivative thereof; N,N'-bis(2-hydroxy-5-sulfobenzyl)ethylenediamine-N,N'-diacetic acid (SHBED) or a derivative thereof; N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HEED) or a derivative thereof; 3,6,9,15-tetraazabicyclo[9.3 1]pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid (PCTA) or a derivative thereof; desferrioxamine B (DFO) or a derivative thereof; N,N'-(methylenephosphonate)-N,N'46-(methoxycarbonyl)pyridin-2-yl]methy1-1,2-diaminoethane (H6phospa) or a derivative thereof; 1,4,7,10,13,16-hexaazacyclohexadecane-N,N',N",N",N"",N'""-hexaacetic acid (HEHA) or a derivative thereof;
1,4,7,10,13-pentaazacyclopentadecane-N,N',N",N"',N""-pentaacetic acid (PEPA) or a derivative thereof; or 3,4,3-L1(1,2-HOPO) or a derivative thereof [0166] According to certain aspects, the targeting agent may be radiolabeled through chemical conjugation of suitable bifunctional chelators that can chelate one or more radionuclides. Exemplary chelator molecules that may be used include p-SCN-Bn-DOTA, NH2-DOTA, NH2-(CH2)1-20-DOTA, NH2-(PEG)3_20-DOTA, HS-DOTA, HS-(CH2)1-20-DOTA, HS-(PEG)1-20-DOTA, dibromo-S-(CH2)1-2o-DOTA, dibromo-S-(PEG)1-20-DOTA, p-SCN-Bn-DOTP, NH2-DOTP, NH2-(CH2)1-20-DOTP, NH2-(PEG)1-20-DOTP, HS-DOTP, HS-(CH2)1-20-DOTP, HS-(PEG)1_20-DOTP, dibromo-S-(CH2)3.20-DOTP, and dibromo-S-(PEG)1.20-DOTP.
[0167] The chelator molecules may, for example, be attached to a targeting agent through a linker molecule. Exemplary linker molecules include:
-CH2(C6H4)NH2 or -CH2(C6H4)NH-X-Y, wherein X is -R2-CH2CH20(CH2CH20)11CH2CH2-, -R2-CH2CH2NHC(0)CH2CH20(CH2CH20)11CH2CH2-, -R2-(CH2)nCH2-, -R2-CH2CH2NHC(0)(CH2)nCH2-, -R2-CH(C(0)R3)CH2-, wherein R3 is -OH or a short peptide (1-20 amino acids), -R2-CH2CH20(CH2CH20)CH2C(0)0-, or -R2-CH2CH2NFIC(0)CH2CH20(CH2CH20)nCH2CC(0)0-, wherein n is 1-20, and R2 is -C(0)- or -C(S)NH-; and Y is -NH2 or -SR4-, wherein R4 is -H or -CH2-3,5-bis(bromomethyl)benzene.
[0168] Targeting agents, such as protein targeting agents, for example antibodies and antigen-binding antibody fragments, and peptide targeting agents may, for example, be conjugated with a chelator for radiolabeling the targeting agent via chelation of a radionuclide.
Such protein or peptide targeting agents, for example, that include lysine(s), may conveniently be conjugated to a DOTA chelating moiety using the bifunctional agent S-2-(4-Isothiocyanatobenzy1)-1,4,7,10-tetraazacyclododecane tetraacetic acid a/k/a/
"p-SCN-Bn-DOTA" (Catalog # B205; Macrocyclics, Inc., Plano, TX, USA). p-SCN-Bn-DOTA may be synthesized by a multi-step organic synthesis fully described in U.S. Patent No. 4,923,985.
Chelation of a radionuclide by the DOTA moiety may be performed prior to chemical conjugation of the antibody with p-SCN-Bn-DOTA and/or after said conjugation.
[0169] Methods for labeling a chelator-conjugated targeting agent with an exemplary radionuclide are described in in Example 1.
[0170] Diagnostic aspects [0171] The presently disclosed methods may include diagnosing the subject to ascertain if HER3-positive cells are present, to what extent they are, and/or their localization. HER3-positive cells may be present in a number of biological specimens, such as in circulating cells in a sample of blood from the subject or tumor cells in a biopsy of the subject.
In one aspect, the diagnosing step may generally include obtaining a sample of blood or tissue from the subject and mounting the sample on a substrate. The presence or absence of the HER3 antigen may be detected using a diagnostic antibody, peptide, or small molecule, wherein the diagnostic antibody peptide, or small molecule is labeled with any of the standard imaging labels known in the art.
Exemplary labeling agents include, for example, radiolabels such as 3H, 14C, 32-, "S, and 1251;
fluorescent or chemiluminescent compounds, such as fluorescein isothiocyanate, rhodamine, or luciferin; and enzymes, such as alkaline phosphatase, 13-gal actosidase, or horseradish peroxidase.
An exemplary HER3 targeting agent used in such a diagnostic assay includes a human or humanized antibody against HER3.
[0172] In another aspect, the methods may include diagnosing the subject to ascertain if HER3-positive cells are present using a HER3 targeting agent labeled with a radionuclide such as any of "F, 11C, "Ga, "Cu, "Zr, or 1241, for PET imaging, or 99Tc or n'In, for SPECT
imaging. Accordingly, the method may include administering to the subject a HER3 targeting agent labeled with one or more of 1-8F, "Ga, 64Cu, "Zr, 1 99mTC, or Win, and performing a non-invasive imaging technique on the subject, such as performing a PET or SPECT scan on the subject. The method may include administering the radiolabeled HER3 targeting agent for imaging to the subject and, after an amount of time sufficient for the targeting agent to bind to target in the subject's tissues, performing the imaging. The amount of time sufficient for the targeting agent to bind to target in the subject's tissues may, for example, be at least 20 minutes, at least 30 minutes, at least 60 minutes, or any number or subrange of minutes in the range 20 minutes to 360 minutes. According to certain one aspect of the method, the radiolabeled HER3 targeting agent may include 68Cia, "Zr, or 1111n, and may be labeled using any of the methods disclosed herein (e.g., such as disclosed in Example 1).
[0173] If the subject has HER3-positive cancer cells, for example, beyond a predetermined or preselected threshold level, or other indications of a HER3-positive cancer/tumor, the therapeutic methods of the presently disclosed invention may be carried out, i.e., administration of a therapeutically effective amount of a radiolabeled 1-IER3 targeting agent, alone or in combination with one or more additional therapeutic agents may be performed.
[0174] Additional therapeutic agents and modalities [0175] The methods of the present invention that include administration of a radiolabeled TIER3 targeting agent therapeutic, alone or in combination with other targeting agents, may further include administration of an additional therapeutic agent or modality.
According to certain aspects, the additional agent may be relevant for the disease or condition being treated by the radiolabeled HER3 targeting agent. Such administration may be simultaneous, separate or sequential with the administration of the effective amount of the HER3 targeting agent. For simultaneous administration, the agents may be administered as one composition, or as separate compositions, as appropriate.
[0176] Exemplary additional therapeutic agents and modalities that may be used in combination or conjunction with a radiolabeled HER3 targeting agent include at least chemotherapeutic agents, small molecule oncology drugs, anti-inflammatory agents, immunosuppressive agents, immunomodulatory agents, include immune checkpoint therapies, DDR inhibitors, CD47 blockades, external beam radiation, brachytherapy, or any combination thereof. Exemplary additional agents and treatment modalities that may be used in combination or conjunction with a radiolabeled HER3 targeting agent alone or in combination other targeting agents as disclosed herein are further described below.
[0177] A. Chemotherapeutic and other small molecule agents [0178] Exemplary chemotherapeutic agents include, but are not limited to, anti-neoplastic agents including alkylating agents including: nitrogen mustards, such as mechlorethamine, cyclophosphamide, ifosfamide, melphalan and chlorambucil;
nitrosoureas, such as carmustine (BCNU), lomustine (CCNU), and semustine (methyl-CCNU);
TemodalTm (temozolomide), ethylenimines/methylmelamine such as thriethylenemelamine tri ethylene, thi ophosph orami de (thi otep a), h ex am ethyl m el amine (TIMM, tretam i n e); alkyl sulfonates such as busulfan; triazines such as dacarbazine (DUO;
antimetabolites including folic acid analogs such as m eth otrex ate and tri m etrex ate, pyri mi dine analogs such as 5-fluorouracil (5FU), fluorodeoxyuridine, gemcitabine, cytosine arabinoside (AraC, cytarabine), 5-azacytidine, 2,2'-difluorodeoxycytidine, purine analogs such as 6-mercaptopurine, 6-thioguamne, azathioprine, T-deoxycoformycin (pentostatin), erythrohydroxynonyladenine (EHNA), fludarabine phosphate, and 2-chlorodeoxyadenosine (cladribine, 2-CdA); natural products including antimitotic drugs such as paclitaxel, vinca alkaloids including vinblastine (VLB), vincristine, and vinorelbine, taxotere, estramustine, and estramustine phosphate;
pipodophylotoxins such as etoposide and teniposide; antibiotics such as actinomycin D, daunomycin (rubidomycin), doxorubicin, mitoxantrone, idarubicin, bleomycins, plicamycin (mithramycin), mitomycin C, and actinomycin; enzymes such as L-asparaginase;
biological response modifiers such as interferon-alpha, IL-2, G-CSF and GM-CSF;
miscellaneous agents including platinum coordination complexes such as oxaliplatin, cisplatin and carboplatin, anthracenediones such as mitoxantrone, substituted urea such as hydroxyurea, methylhydrazine derivatives including N-methylhydrazine (MIH) and procarbazine, adrenocortical suppressants such as mitotane (o, p-DDD) and aminoglutethimide; hormones and antagonists including adrenocorti costeroi d antagonists such as predni sone and equivalents, dex am ethason e and aminoglutethimide; GemzarTM (gemcitabine), progestin such as hydroxyprogesterone caproate, medroxyprogesterone acetate and megestrol acetate; estrogen such as diethylstilbestrol and ethinyl estradiol equivalents; antiestrogen such as tamoxifen, androgens including testosterone propionate and fluoxymesterone/equivalents; anti androgens such as flutami de, gonadotropin-releasing hormone analogs and leuprolide; and non-steroidal antiandrogens such as flutamide.
[0179] Therapies targeting epigenetic mechanisms including, but not limited to: (i) histone deacetylase (HDAC) inhibitors such as Vorinostat (suberoylanilide hydroxamic acid;
SAHA), Romidepsin, Belinostat (PDX101), Panobinostat (LBH589) and Tucidinostat, demethylating agents (e.g., Vidaza); (ii) LSD1 inhibitors such as seclidemstat, TCP
(tranylcypromine), ORY-1001 (iadademstat), GSK2879552 (GSK), INCB059872 (Imago BioSciences), IMG-7289 (Bomedemstat; Imago BioSciences), ORY-2001 (Vafidemstat), and CC-90011 (Celgene); and (iii) release of transcriptional repression (ATRA) therapies, may also be used in combination or conjunction with a radiolabeled HER3 targeting agent and/or other radiolabeled targeting agents and combinations thereof as disclosed herein.
[0180] According to certain aspects of the present invention, the chemotherapeutic agents include at least radiosensitizers, such as temozolomide, cisplatin, and/or fluorouracil.
[0181] The additional agents may, for example, include a bc1-2 inhibitor such as navitoclax or venetoclax (Venelexta ; Abbvie) and the combination may, for example, be used for the treatment of solid tumors such as breast cancers and lunger cancer such as small cell lung carcinoma (SCLC).
[0182] The additional agents may, for example, include a cyclin-dependent kinase CDK4 and CDK6 inhibitor such as palbociclib (Ibrancee; Pfizer) and the combination may, for example, be used for the treatment of solid cancers such as breast cancers such as HR-positive and HER2-negative breast cancer, with or without an aromatase inhibitor.
[01831 The additional agents may, for example, include erlotinib (Tarceva0;
Roche) and the combination may, for example, be used for the treatment of solid tumor cancers such as non-small cell lung cancer (NSCLC), for example, with mutations in the epidermal growth factor receptor (EGFR) and pancreatic cancer.
[0184] The additional agents may, for example, include sirolimus or everolimus (Affinitore; Novartis) and the combination may, for example, be used for the treatment of solid tumor cancers such as melanoma and breast cancer.
[0185] The additional agents may, for example, include pemetrexed (Alimtag;
Eli Lilly) and the combination may, for example, be used for the treatment of solid cancers such as mesothelioma such as pleural mesothelioma and lung cancer such as non-small cell lung cancer (NSCLC).
[01861 The additional therapeutic agents may, for example, be administered according to any standard dose regime known in the field. For example, therapeutic agents may be administered at concentrations in the range of 1 to 500 mg/m2, the amounts being calculated as a function of patient surface area (m2). For example, exemplary doses of the chemotherapeutic paclitaxel may include 15 mg/m2 to 275 mg/m2, exemplary doses of docetaxel may include 60 mg/m2 to 100 mg/m2, exemplary doses of epithilone may include 10 mg/m2 to 20 mg/m2, and an exemplary dose of calicheamicin may include 1 mg/m2 to 10 mg/m2. While exemplary doses are listed herein, such are only provided for reference and are not intended to limit the dose ranges of the drug agents of the presently disclosed invention.
[01871 R. External Ream Radiation and/or Braelatherapv [0188] The additional therapeutic modality administered in conjunction with the HER3 targeting agent, and optionally any other of the additional therapeutics disclosed herein, may be an ionizing radiation, such as administered via external beam radiation or brachytherapy. Such radiation generally refers to the use of X-rays, gamma rays, or charged particles (e.g., protons or electrons) to generate ionizing radiation, such as delivered by a machine placed outside the patient's body (external-beam radiation therapy) or by a source placed inside a patient's body (internal radiation therapy or brachytherapy).
[0189] The external beam radiation or brachytherapy may enhance the targeted radiation damage delivered by the radiolabeled 1-IER3 targeting agent and may thus be delivered sequentially with the HER3 targeting agent, such as before and/or after the HER3 targeting agent, or simultaneous with the HER3 targeting agents.
[0190] The external beam radiation or brachytherapy may be planned and administered in conjunction with imaging-based techniques such as computed tomography (CT) and/or magnetic resonance imaging (MRI) to accurately determine the dose and location of radiation to be administered. For example, a patient treated with any of the radiolabeled HER3 targeting agents disclosed herein may be imaged using either of CT or MRI to determine the dose and location of radiation to be administered by the external beam radiation or brachytherapy.
[0191] In various embodiments, the radiation therapy may be selected from the group consisting of total all-body radiation therapy, conventional external beam radiation therapy, stereotactic radiosurgery, stereotactic body radiation therapy, 3-D conformal radiation therapy, intensity-modulated radiation therapy, image-guided radiation therapy, tomotherapy, and brachytherapy. According to certain aspects, the radiation therapy may be provided as a single dose or as fractionated doses, e.g., as 2 or more fractions. For example, the dose may be administered such that each fraction includes 2-20 Gy (e.g., a radiation dose of 50 Gy may be split up into 10 fractions, each including 5 Gy). The 2 or more fractions may be administered on consecutive or sequential days, such as once in 2 days, once in 3 days, once in 4 days, once in 5 days, once in 6 days, once in 7 days, or in a combination thereof.
[0192] C. Immune Checkpoint Therapies [0193] The additional agent(s) administered in conjunction with the HER3 targeting agent may be an immune checkpoint therapy. Cancer cells have developed means to evade the standard checkpoints of the immune system. For example, cancer cells have been found to evade immunosurveillance through reduced expression of tumor antigens, downregulation of 1VIEIC
class I and II molecules leading to reduced tumor antigen presentation, secretion of immunosuppressive cytokines such as TGFb, recruitment or induction of immunosuppressive cells such as regulatory T cells (Treg) or myeloid-derived suppressor cells (MDSC), and overexpression of certain ligands [e.g., programmed death ligand-1 (PD-L1)]
that inhibit the host's existing antitumor immunity.
[0194] Another major mechanism of immune suppression by cancer cells is a process known as "T-cell exhaustion", which results from chronic exposure to tumor antigens, and is characterized by the upregulation of inhibitory receptors. These inhibitory receptors serve as immune checkpoints in order to prevent uncontrolled immune reactions.
[0195] Various immune checkpoints acting at different levels of T cell immunity have been described in the literature, including PD-1 (i.e., programmed cell death protein 1) and its ligands PD-Li and PD-L2, CTLA-4 (i.e., cytotoxic T-lymphocyte associated protein-4) and its ligands CD80 and CD86, LAG3 (i.e., Lymphocyte-activation gene 3), B and T
lymphocyte attenuator, TIGIT (T-cell immunoreceptor with Ig and ITIM domains), TIM-3 (i.e., T-cell immunoglobulin and mucin-domain containing protein 3), and VISTA (V-domain immunoglobulin suppressor of T cell activation).
[0196] Enhancing the efficacy of the immune system by therapeutic intervention is a particularly exciting development in cancer treatment. As indicated, checkpoint inhibitors such as CTLA-4 and PD-1 prevent autoimmunity and generally protect tissues from immune collateral damage. In addition, stimulatory checkpoints, such as 0X40 (i.e., tumor necrosis factor receptor superfamily, member 4; TNFR-SF4), CD137 (i.e., TNFR-SF9), GITR (i.e., Glucocorticoid-Induced TNFR), CD27 (i.e., TNFR-SF7), CD40 (i.e., cluster of differentiation 40), and CD28, activate and/or promote the expansion of T-cells. Regulation of the immune system by inhibition or overexpression of these proteins is an area of promising current research.
[01971 Thus, a promising therapeutic strategy is the use of immune checkpoint therapies that may remove certain blockades on the immune system that are utilized by cancer cells, in combination with the HER3 targeting agents disclosed herein. For example, antibodies against certain immune checkpoint inhibitors (ICI) may block interaction between checkpoint inhibitor proteins and their ligands, therefore preventing the signaling events that would otherwise have led to inhibition of an immune response against the tumor cell.
[0198] Moreover, there is a growing body of preclinical evidence supporting the ability of radiation to synergize with ICI antibodies, and this is also being explored in the clinic with increasing numbers of clinical trials evaluating the combination of external beam radiation with immune checkpoint therapies across various tumor types and ICI antibodies (Lamichhane, 2018).
Clinical evidence supporting this combination has been generated in melanoma, with two studies demonstrating a clinical benefit using radiation in combination with the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) ICI antibody, Ipilimumab (Tvvyman-Saint Vistor, 2015).
[0199] Accordingly, an object of the presently disclosed invention is to provide therapies for the treatment of cancer using a HER3 targeting agent in combination with one or more immune checkpoint therapies, such as an ICI antibody.
[0200] Immune checkpoint therapies of the present invention include molecules that totally or partially reduce, inhibit, interfere with or modulate one or more checkpoint proteins.
Checkpoint proteins regulate T-cell activation or function. Immune checkpoint therapies may unblock an existing immune response inhibition by binding to or otherwise disabling checkpoint inhibition. The immune checkpoint therapies may include monoclonal antibodies, humanized antibodies, fully human antibodies, antibody fragments. small molecule therapeutics, or a combination thereof.
[0201] Exemplary immune checkpoint therapies may specifically bind to and inhibit a checkpoint protein, such as the inhibitory receptors CTLA-4, PD-1, TIM-3, VISTA, BTLA, LAG-3 and TIGIT, and/or the activating receptors CD28, 0X40, CD40, GITR, CD137, CD27, and HVEM. Additionally, the immune checkpoint therapy may bind to a ligand of any of the aforementioned checkpoint proteins, such as PD-L1, PD-L2, PD-L3, and PD-L4 (ligands for PD-1); CD80 and CD86 (ligands for CTLA-4); CD137-L (ligand of CD137); and GITR-L
(ligand of GITR). Other exemplary immune checkpoint therapies may bind to checkpoint proteins such as CD226, B7-H3, B7-H4, BTLA, TIGIT, GALS, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, 76, and memory CD 8-I- (a3) T cells), CD160 (also referred to as BY55), and CGEN-15049 102021 Central to the immune checkpoint process are the CD137, C1LA-4 and PD-1 immune checkpoint pathways.
[0203] The CTLA-4 and PD-1 pathways are thought to operate at different stages of an immune response. CTLA-4 is considered the "leader" of the immune checkpoint inhibitors (ICI), as it stops potentially autoreactive T cells at the initial stage of naive T-cell activation, typically in lymph nodes. The PD-1 pathway regulates previously activated T cells at the later stages of an immune response, primarily in peripheral tissues. Moreover, progressing cancer patients have been shown to lack upregulation of PD-Li by either tumor cells or tumor-infiltrating immune cells. Immune checkpoint therapies targeting the PD-1 pathway might thus be especially effective in tumors where this immune suppressive axis is operational and reversing the balance towards an immune protective environment would rekindle and strengthen a pre-existing anti-tumor immune response. PD-1 blockade can be accomplished by a variety of mechanisms including antibodies that bind PD-1 or its ligand, PD-Li.
[0204] According to certain aspects of the presently disclosed invention, the immune checkpoint therapy may include an inhibitor of the PD-1 checkpoint, which may decrease, block, inhibit, abrogate, or interfere with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-Li and PD-L2. The inhibitor of the PD-1 checkpoint may be an anti-PD-1 antibody, antigen binding fragment, fusion proteins, oligopeptides, and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-Li and/or PD-L2.
In some embodiments, a PD-1 checkpoint inhibitor reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some embodiments, the PD-1 checkpoint therapy is an anti-PD-1 antibody.
[0205] Thus, according to certain aspects of the present invention, the immune checkpoint therapy may include a monoclonal antibody against an immune checkpoint inhibitor (ICI) such as against CTLA-4, PD-1, or PD-Li.
[0206] According to certain aspects, the ICI antibody may be an antibody against PD-1.
The ICI antibody may be an anti-PD-1 antibody, such as nivolumab. For example, the inhibitors of PD-1 biological activity (or its ligands) disclosed in U.S. Pat. No.
7,029,674. Exemplary antibodies against PD-1 include: Anti-mouse PD-1 antibody Clone J43 (Cat #BE0033-2) from BioXcell; Anti-mouse PD-1 antibody Clone RN1P1-14 (Cat #BE0146) from BioXcell;
mouse anti-PD-1 antibody Clone EH12; Merck's MK-3475 anti-mouse PD-1 antibody (Keytruda , pembrolizumab, lambrolizumab); and AnaptysBio's anti-PD-1 antibody, known as ANB011;
antibody MDX-1 106 (ONO-4538); Bristol-Myers Squibb's human IgG4 monoclonal antibody nivolumab (Opdivog, BMS-936558, MDX1106); AstraZeneca's A1\4P-514, and AMP-224; and Pidilizumab (CT-011), CureTech Ltd.
[0207] According to certain aspects, the immune checkpoint therapy is an inhibitor of PD-Li. Exemplary inhibitors of PD-Li include antibodies (e.g., an anti-PD-Li antibody, i.e., ICI
antibody), RNAi molecules (e.g., anti-PD-Li RNAi), antisense molecules (e.g., an anti-PD-Li antisense RNA), dominant negative proteins (e.g., a dominant negative PD-Li protein), and small molecule inhibitors. An exemplary anti-PD-Li antibody includes clone EH12. Exemplary antibodies against PD-Li include: Genentech's MPDL3280A (RG7446); anti-mouse PD-Li antibody Clone 10F 9G2 (Cat #BE0101) from BioXcell; anti-PD-Li monoclonal antibody MDX-1105 (BMS-936559) and BMS-935559 from Bristol-Meyer's Squibb; MSB0010718C;
mouse anti-PD-Li Clone 29E.2A3; and AstraZeneca's MEDI4736 (Durvalumab).
[0208] According to certain aspects, the immune checkpoint therapy is an inhibitor of PD-L2 or may reduce the interaction between PD-1 and PD-L2 Exemplary inhibitors of PD-L2 include antibodies (e.g., an anti-PD-L2 antibody, i.e., ICI antibody), RNAi molecules (e.g., an anti-PD-L2 RNAi), antisense molecules (e.g., an anti-PD-L2 antisense RNA), dominant negative proteins (e.g., a dominant negative PD-L2 protein), and small molecule inhibitors. Antibodies include monoclonal antibodies, humanized antibodies, deimmunized antibodies, and Ig fusion proteins.
[0209] According to certain aspects, the immune checkpoint therapy may be an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody, i.e., ICI antibody. According to one aspect, the ICI antibody may be ipilimumab. The anti-CTLA-4 antibody may block the binding of CTLA-4 to CD80 (B7-1) and/or CD86 (B7-2) expressed on antigen presenting cells.
Exemplary antibodies against CTLA-4 include: Bristol Meyers Squibb's anti-CTLA -4 antibody ipilimumab (also known as Yervoyg, MDX-010, BMS-734016 and MDX-101); anti-CTLA4 Antibody, clone 9H10 from Millipore; Pfizer's tremelimumab (CP-675,206, ticilimumab);
and anti-CTLA-4 antibody clone BNI3 from Abcam. According to certain aspects, the immune checkpoint inhibitor may be a nucleic acid inhibitor of C1LA-4 expression.
[0210] CD137 (also known "TNF receptor superfamily member 9") is a costimulatory receptor member of the tumor necrosis factor receptor superfamily, mediating CD28-dependent and independent T-cell co-stimulation (Bartkowiak, 2015). CD137 is inducibly expressed by T
cells, natural killer (NK) cells, dendritic cells (DC), B cells, and other cells of the immune system. The protein is composed of a 255-amino acid protein having a short N-terminal cytoplasmic portion, a transmembrane region, and an extracellular domain that possesses 3 cysteine-rich motifs. Ligation of CD137 by its ligand CD137L (4-1BBL; TNF
SF9), which is mainly, though not exclusively, expressed on Antigen-Presenting Cells (APCs), evokes various T
cell responses such as cell expansion, increased cytokine secretion and the prevention of activation-induced cell death. Thus, such ligation serves to activate the immune system.
However, cis-interactions between CD137 and CD137L also potently downregulate the expression of' CD137L (Kwon, 2015). The CD137 ligand thus functions to control the extent and kinetics of CD137-mediated immune system activation (Kwon, 2015).
Significantly, CD137 expressed on human NK cells becomes upregulated upon binding to anti-tumor antibodies that have become bound to tumor cells (Wei, 2014).
[0211] Thus, according to certain aspects of the presently disclosed invention, the immune checkpoint therapy may include an antibody against CD137, which could be used to activate the immune system and thereby provide a therapy for cancer in combination with the presently disclosed HER3 targeting agents. Exemplary anti-CD137 antibodies that may be used are disclosed in U.S. Publication Nos. 20140274909; 20130280265; 20130273078;
20130071403; 20120058047, 20110104049; 20110097313; 20080166336; 20080019905;
20060188439; 20060182744; 20060121030; and 20030223989.
[0212] According to certain aspects of the present invention, the immune checkpoint therapy may include more than one modulator of an immune checkpoint protein.
As such, the immune checkpoint therapy may include a first antibody or inhibitor against a first immune checkpoint protein and a second antibody or inhibitor against a second immune checkpoint protein.
[0213] D. DNA Damnee Response inhibitors [0214] The additional agents administered in conjunction with the HER3 targeting agent may be one or more DNA damage response inhibitors (DDRi). DNA damage can be due to endogenous factors, such as spontaneous or enzymatic reactions, chemical reactions, or errors in replication, or may be due to exogenous factors, such as UV or ionizing radiation or genotoxic chemicals. The repair pathways that overcome this damage are collectively referred to as the DNA damage response or DDR. This signaling network acts to detect and orchestrate a cell's response to certain forms of DNA damage, most notably double strand breaks and replication stress. Following treatment with many types of DNA damaging drugs and ionizing radiation, cells are reliant on the DDR for survival. It has been shown that disruption of the DDR can increase cancer cell sensitivity to these DNA damaging agents and thus may improve patient responses to such therapies.
[0215] Within the DDR, there are several DNA repair mechanisms, including base excision repair, nucleotide excision repair, mismatch repair, homologous recombinant repair, and non-homologous end joining. Approximately 450 human DDR genes code for proteins with roles in physiological processes. Dysregulation of DDR leads to a variety of disorders, including genetic, neurodegenerative, immune, cardiovascular, and metabolic diseases or disorders and cancers. For example, the genes OGG1 and XRCC1 are part of the base excision repair mechanism of DDR, and mutations in these genes are found in renal, breast, and lung cancers, while the genes BRCA1 and BRCA2 are involved in homologous recombination repair mechanisms and mutations in these genes leads to an increased risk of breast, ovarian, prostate, pancreatic, as well as gastrointestinal and hematological cancers, and melanoma. Exemplary DDR genes are provided in Table 3.
[02161 An object of the presently disclosed invention is to administer radiolabeled FIER3 targeting agents that deliver ionizing radiation in combination with a DDRi.
Thus, according to certain aspects, the additional agent(s) administered with the HER3 targeting agent may target proteins in the DDR, i.e., DDR inhibitors or DDRi, thus maximizing DNA damage or inhibiting the repair if the damage, such as in G1 and S-phase and/or preventing repair in G2, ensuring the maximum amount of DNA damage is taken into mitosis, leading to cell death.
DNA repair Gene Cancer mechanism examples Base Excision OGG/ Renal, breast and lung cancer Repair XRCC 1 Non-small cell lung cancer ERCC I Lung and skin cancer, and glioma Nucleotide Xeroderma pigmentosum predisposing to skin cancer.
Excision Repair XP
Also increased risk of bladder and lung cancer Lynch syndrome predisposing to colorectal cancer as well MSH2, as endometrial, ovarian, stomach, small intestine, Mismatch Repair MLHJ hepatobiliary tract, upper urinary tract, brain and skin cancer Homologous BRCA I Increased risk of breast, ovarian, prostate, pancreatic, as , Recombinant BRCA 2 well as gastrointestinal and hematological cancer, and Repair melanoma Non-homologous KU70 Breast, colorectal and lung cancer End Joining KUSO Lung cancer Cell cycle AIM Ataxia-telangiectasia predisposing to leukemia, breast and pancreatic cancer checkpoints AIR Leukemia, lymphoma, gastric and endometrial cancer [0217] Moreover, one or more DDR pathways may be targeted to ensure cell death, i.e., lethality to the targeted cancer cells. For example, mutations in the BRCA1 and 2 genes alone may not be sufficient to ensure cell death, as other pathways, such as the PARP1 base excision pathway, may act to repair the DNA damage. Thus, combinations of multiple DDRi inhibitors or combining DDRi with antiangiogenic agents or immune checkpoint inhibitors, such as listed hereinabove, are possible and an object of the presently disclosed invention.
[02181 Exemplary DDRi ¨ATM and ATR inhibitors [0219] Ataxia telangiectasia mutated (ATM) and Ataxia talangiectasia mutated and Rad-3 related (ATR) are members of the phosphatidylinositol 3-kinase-related kinase (PIKK) family of serine/threonine protein kinases.
[02201 ATM is a serine/threonine protein kinase that is recmited and activated by DNA
double-strand breaks. The ATM phosphorylates several key proteins that initiate activation of a DNA damage checkpoint, leading to cell cycle arrest, DNA repair, or cellular apoptosis. Several of these targets, including p53, CHK2, and H2AX, are tumor suppressors. The protein is named for the disorder ataxia telangiectasia caused by mutations of the ATM. The ATM
belongs to the superfamily of phosphatidylinositol 3-kinase-related kinases (PIKKs), which includes six serine/threonine protein kinases that show a sequence similarity to a phosphatidylinositol 3-kinase (PI3K).
[02211 Like ATM, ATR is one of the central kinases involved in the DDR. ATR is activated by single stranded DNA structures, which may for example arise at resected DNA
DSBs or stalled replication forks. When DNA polymerases stall during DNA
replication, the replicative helicases continue to unwind the DNA ahead of the replication fork, leading to the generation of long stretches of single stranded DNA (ssDNA).
[0222] ATM has been found to assist cancer cells by providing resistance against chemotherapeutic agents and thus favors tumor growth and survival. Inhibition of ATM and/or ATR may markedly increase cancer cell sensitivity to DNA damaging agents, such as the ionizing radiation provided by the radiolabeled HER3 targeting agent.
Accordingly, an object of the presently disclosed invention includes administration of an inhibitor of ATM (ATMi) and/or ATR (ATRi), in combination with the HER3 targeting agents, to inhibit or kill cancer cells, such as those expressing tor overexpressing HER3.
[0223] The inhibitor of ATM (ATMi) or ATR (ATRi) may be an antibody, peptide, or small molecule that targets ATM or ATR, respectively. Alternatively, an ATMi or ATRi may reduce or eliminate activation of ATM or ATR by one or more signaling molecules, proteins, or other compounds, or can result in the reduction or elimination of ATM or ATR
activation by all signaling molecules, proteins, or other compounds. ATMi and/or ATRi also include compounds that inhibit their expression (e.g., compounds that inhibit ATM or ATR
transcription or translation). An exemplary ATMi KU-55933 suppresses cell proliferation and induces apoptosis.
Other exemplary ATMi include at least KU-59403, wortmannin, CP466722, and KU-60019.
Exemplary ATRi include at least Schisandrin B, NU6027, NVP-BEA235, VE-821, VE-822, AZ20, and AZD6738.
[0224] Exemplary DDRi ¨ Weel inhibitors [02251 The checkpoint kinase Weel catalyzes an inhibitory phosphorylation of both CDK1 (CDC2) and CDK2 on tyrosine 15, thus arresting the cell cycle in response to extrinsically induced DNA damage. Deregulated Weel expression or activity is believed to be a hallmark of pathology in several types of cancer. For example, Weel is often overexpressed in glioblastomas, malignant melanoma, hepatocellular carcinoma, breast cancer, colon carcinoma, lung carcinoma, and head and neck squamous cell carcinoma. Advanced tumors with an increased level of genomic instability may require functional checkpoints to allow for repair of such lethal DNA damage. As such, the present inventors believe that Weel represents an attractive target in advanced tumors where its inhibition is believed to result in irreparable DNA
damage. Accordingly, an object of the presently disclosed invention includes administration of an inhibitor of Weel, in combination with the 1-IER3 targeting agents, to inhibit or kill cancer cells, such as those expressing tor overexpressing HER3.
[0226] A Weel inhibitor may be an antibody, peptide, or small molecule that targets Weel. Alternatively, a Weel inhibitor may reduce or eliminate Weel activation by one or more signaling molecules, proteins, or other compounds, or can result in the reduction or elimination of Weel activation by all signaling molecules, proteins, or other compounds.
The term also includes compounds that decrease or eliminate the activation or deactivation of one or more proteins or cell signaling components by Weel (e.g., a Weel inhibitor can decrease or eliminate Weel-dependent inactivation of cyclin and Cdk activity). Weel inhibitors also include compounds that inhibit Weel expression (e.g., compounds that inhibit Weel transcription or translation).
[0227] Exemplary Weel inhibitors include AZD-1775 (i.e., adavosertib), and inhibitors such as those described in, e.g., U.S. Patent Nos, 7,834,019; 7,935,708;
8,288,396; 8,436,004;
8,710,065; 8,716,297; 8,791,125; 8,796,289; 9,051,327; 9,181,239; 9,714,244;
9,718,821; and 9,850,247; U.S. Pub. Nos. US 20100113445 and 20160222459; and International Pub. Nos.
W02002090360, 2015019037, 2017013436, 2017216559, 2018011569, and 2018011570.
[0228] Further Weel inhibitors include a pyrazolopyrim i din e derivative, a pyridopyrimidine, 4-(2-chloropheny1)-9-hydroxypyrrolo[3,4-c]carbazole-1,3-(2H, 6H)-dione (CAS No. 622855-37-2), 6-buty1-4-(2-chloropheny1)-9-hydroxypyrrolo[3,4-c]carbazole-1,3-(2H,6H)-dione (CAS No. 62285550-9), 4-(2-pheny1)-9-hydroxypyrrolo[3,4-c]carbazole-1,3-(2H,6H)-dione (CAS No. 1177150-89-8), and an anti-Weel small interfering RNA
(siRNA) molecule.
[0229] Exemplary DDRi - PARP inhibitors [0230] Another exemplary type of DDRi that may be used are inhibitors of poly(ADP-ribose) polymerase ("PARP"). Inhibitors of the DNA repair protein PARP, referred to individually and collectively as "PARPi", have been approved for use in a range of solid tumors, such as breast and ovarian cancer, particularly in patients having BRCA1/2 mutations. BRCA1 and 2 function in homologous recombination repair (HRR). When mutated, they induce genomic instability by shifting the DNA repair process from conservative and precise HRR to non-fidelitous methods such as DNA endjoining, which can produce mutations via deletions and insertions.
[0231] PARPi have been shown to exhibit synthetic lethality, as exhibited by potent single agent activity, in BRCA1/2 mutant cells. This essentially blocks repair of single-strand DNA breaks. Since 1-112,1t is not functional in these tumor cells, cell death results. Because most tumors do not carry BRCA1 or BRCA2 mutations, the potency of PARPi in such tumors is far less pronounced.
[0232] To date, the FDA has approved four PARPi drugs (olaparib, niraparib, rucaparib and talazoparib) as monotherapy agents, specifically in patients with germline and somatic mutations in the BRCA1 and BRCA2 genes. Along with veliparib, olaparib, niraparib and rucaparib were among the first generation of PARPi that entered clinical trials. Their IC50 values were found to be in the nanomolar range. In contrast, second generation PARPi like talazoparib have IC50 values in the picomolar range.
[0233] These PARPi all bind to the binding site of the cofactor, b nicotinamide adenine dinucleotide (b-NAD+), in the catalytic domain of PARP1 and PARP2. The PARP
family of enzymes use NAD+ to covalently add Poly(ADP-ribose) (PAR) chains onto target proteins, a process teitned "PARylation.- PARP1 (which is the best-studied member) and PARP2, are important components of the DNA damage response (DDR) pathway, PARP1 is involved in the repair of single-stranded DNA breaks, and possibly other DNA lesions (Woodhouse, et al.;
Krishnakumar, et al.). Through its zinc finger domains, PARP1 binds to damaged DNA and then PARylates a series of DNA repair effector proteins, releasing nicotinamide as a by-product (Krishnakumar, et al.). Subsequently, PARP I auto-PARylation leads to release of the protein from the DNA. The available PARPi, however, differ in their capability to trap PARP1 on DNA, which seems to correlate with cytotoxicity and drug efficacy. Specifically, drugs like talazoparib and olaparib are more effective in trapping PARP1 than are veliparib (Murai, et al., 2012; Murai, et al., 2014).
[0234] The efficacy of PARPi in ovarian cancer and breast cancer patients who have loss-of-function mutations in BRCA1 or BRCA2 genes is largely attributed to the genetic concept of synthetic lethality. that proteins of BRCA 1 and 2 normally maintain the integrity of the genome by mediating a DNA repair process, known as homologous recombination repair (HRR); and PARPi causes a persistent DNA lesion that, normally, would otherwise be repaired by HR. In the presence of PARPi, PARP1 is trapped on DNA which stalls progression of the replication fork. this stalling is cytotoxic unless timely repaired by the filt system. In cells lacking effective HR, they are unable to effectively repair these DNA lesions, and thus die.
[0235] Again, mutations in BRCA genes and others in the 1-1R,R system are not prevalent in many cancer types. So, to better harness the therapeutic benefits of PARPi in such cancers, one can induce "artificial- synthetic lethality by pairing a PARPi with either chemotherapy or radiation therapy. Preclinical studies have demonstrated that combining radiation therapy and PARPi can increase the sensitivity of BRCA1/2 mutant tumor cells to PARP
inhibition and extend the sensitivity of non-mutant BRCA tumors to PARP inhibition.
Additional studies have shown that ionizing radiation (lift) itself can mediate PARPi synthetic lethality in tumor cells.
[0236] Accordingly, an object of the presently disclosed invention is to administer radiolabeled HER3 targeting agents that deliver ionizing radiation in combination with a PARPi.
[0237] In the various embodiments of this invention, the PARPi may be any known agent performing that function, and preferably, one approved by the FDA. Preferably, the PARPi is olaparib (Lynparza0), niraparib (Zejula8), rucaparib (Rubracag) or talazoparib (Talzenna8).
[0238] Clinically, therapy with PARPi has resulted in sustained anti-tumor responses in a range of cancers including ovarian, prostate, pancreatic, and triple-negative breast cancers (TNBC). In one clinical trial, TNBC patients with germline BRCA1/2 mutations were treated with the PARPi, olaparib. While this therapy demonstrated a higher disease stabilization rate in BRCA1/2-mutant compared to non-mutant patients, there were no sustained responses achieved in either cohort (Gelmon, 2011).
[0239] The present inventors realized that the effect of PARPi may be improved through increases in dsDNA breaks induced by ionizing radiation provided by a RER3 targeting agent while these repair pathways are being blocked by the PARPi. Exemplary PARPi include olaparib, niraparib, rucaparib and talazoparib.
[0240] E. CD47 blockades [0241] The additional agents administered with the HER3 targeting agent may be a CD47 blockade, such as any agent that interferes with, or reduces the activity and/or signaling between CD47 (e.g., on a target cell) and SIRPa (e.g., on a phagocytic cell) through interaction with either CD47 or SIRPa. Non-limiting examples of suitable CD47 blockades include CD47 and/or STRPa reagents, including without limitation SIRPa polypepti des, anti-STRPa antibodies, soluble CD47 polypeptides, and anti-C1147 antibodies or antibody fragments.
[0242] Additional examples of a CD47 blockade include agents that modulate the expression of CD47 and/or SIRPa. For example, such agents may include nucleic acid approaches such as phosphorodiamidate morpholino oligomers (PMO) that block translation of CD47 or antibodies specific for human CD47 that modulate, e.g., block, inhibit, reduce, antagonize, neutralize or otherwise interfere with CD47 expression. The CD47 antibodies or anti-sense approaches may inhibit CD47 expression (e.g., inhibiting cell surface expression of CD47), activity, and/or signaling, or may interfere with the interaction between CD47 and SIRPa. The agents provided herein completely or partially reduce or otherwise modulate CD47 expression or activity upon binding to, or otherwise interacting with, CD47, e.g., a human CD47.
The reduction or modulation of a biological function of CD47 is complete, significant, or partial upon interaction between the antibodies and the human CD47 polypeptide and/or peptide. The agents are considered to inhibit CD47 expression or activity when the level of CD47 expression or activity in the presence of the antibody is decreased by at least 50%, e.g., by 60%, 70%, 80%, 90%, 95%, 96%, 98%, 99%, or 100% as compared to the level of CD47 expression or activity in the absence of interaction, e.g., binding, with the antibody described herein.
[0243] According to certain aspects, an anti-CD47 agent is an antibody that specifically binds CD47 (i.e., an anti-CD47 antibody) and reduces the interaction between CD47 on one cell (e.g., an infected cell) and S1RPa, on another cell (e.g., a phagocytic cell).
Non-limiting examples of suitable antibodies include clones B6H12, 5F9, 8B6, and C3 and any of those described in International Pub. No. W02011/143624 and U.S. Pub 20210246206. Suitable anti-antibodies include fully human, humanized or chimeric versions of such antibodies.
[0244] Exemplary human or humanized antibodies especially useful for in vivo applications in humans due to their low antigenicity include at least monoclonal antibodies against CD47, such as Hu5F9-G4, a humanized monoclonal antibody available from Gilead as Magrolimab (Sikic, et al. (2019) Journal of Clinical Oncology 37:946);
Lemzoparlimab and TJC4 from I-Mab Biopharma; A0-176 from Arch Oncology, Inc; AK117 from Akesobio Australia Pty; IMC-002 from Innovent Biologics; ZL-1201 from Zia Lab; SHR-1603 from Jiangsu HengRui Medincine Co.; and SRF231 from Surface Oncology. Bispecific monoclonal antibodies are also available, such as IBI-322, targeting both CD47 and PD-L1 from Innovent Biologics. Antibodies against SIRPa are also possible, such as ALX148 from Alx Oncology; B1 765063 (OSE-172) from OSE; as well as small molecule inhibitors, such as RRx-001 (1-bromoacetyl- 3,3 dinitroazetidine) from EpicentRx and Azelnidipine (CAS number 7) or pharmaceutically acceptable salts thereof. See also Table 4 for further description of exemplary agents.
Company Approach Agent/Program Akesobio Australia Pty Ltd CD47 mAb AK117 Arch Oncology (Tioma Therapeutics) CD47 mAb A0-176 Elpiscience Biopharma Inc. CD47 ES004 EpicentRx Small molecule inhibitor RRx-001 of dinitroazetidine (1-bromoacetyl-3,3 hypoxia sensor to dinitroazetidine) downregulate CD47/SlRPct ImmuneOncia Therapeutics CD47 mAb human IMC-002 Innovent Biologics CD47 mAb IBI-188 (CD47 mAb) CD47/PD-L1 bispecific IBI-322 (Bispecific) mAb OSE SIRPct mAb B1765063 (OSE-172) Zai Lab CD47 mAb ZL-1201 Aix Oncology High-affinity SIRPa-Fc ALX148 Gilead/Forty Seven CD47 mAb Magrolimab F SI-SlRPot mAb I-Mab Biopharma CD47 mAb TJC4 Jiangsu HengRui Medicine Co., Ltd. CD47 mAb SHR-1603 Surface Oncology CD47 mAb human SRF231 Morphiex CD47 targeting MBT-001 phosphorodiamidate morpholino oligomers [0245] A0-176, in addition to inducing tumor phagocytosis through blocking the SIRPa interaction, is reported to preferentially bind tumor cells versus normal cells (particularly RBCs where binding is negligible) and directly kills tumor versus normal cells.
[0246] According to certain aspects, a SIRPa reagent may include the portion of SIRPa that is sufficient to bind CD47 at a recognizable affinity, which normally lies between the signal sequence and the transmembrane domain, or a fragment thereof that retains the binding activity.
A suitable S1RPa reagent reduces (e.g., blocks, prevents, etc.) the interaction between the native proteins S1RPa and CD47. For example, the CD47 blocking agent used in various aspects of the invention may be any of those disclosed in U.S. Patent No. 9,969,789 including but not limited to the S1RPa-IgG Fc fusion proteins disclosed therein, such as TTI-621 and TTI-622, both of which preferentially bind CD47 on tumor cells while also engaging activating Fc receptors. A
SERPa-IgG Fc fusion protein including the amino acid sequence SEQ ID NO:116, SEQ ID
NO:117, or SEQ ID NO:118 may, for example, be used.
[0247] Therapeutically effective doses of an anti-CD47 antibody or other protein CD47 inhibitor may be a dose that leads to sustained serum levels of the protein of about 40 pg/ml or more (e.g., about 50 ug/ml or more, about 60 ug/ml or more, about 75 ug/ml or more, about 100 ug/ml or more, about 125 ug/ml or more, or about 150 ug/ml or more).
Therapeutically effective doses or administration of a CD47 blockade, such as an anti-CD47 antibody or SIRPa fusion protein or small molecule, include, for example, amounts of 0.05 - 10 mg/kg (agent weight/subject weight), such as at least 0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 1.5 mg/kg, 2.0 mg/kg, 2.5 mg/kg. 3.0 mg/kg, 3.5 mg/kg, 4.0 mg/kg, 4.5 mg/kg, 5.0 mg/kg, 5.5 mg/kg, 6.0 mg/kg, 6.5 mg/kg, 7.0 mg/kg, 7.5 mg/kg, 8.0 mg/kg, 8.5 mg/kg, 9.0 mg/kg; or not more than 10 mg/kg, 9.5 mg/kg, 9.0 mg/kg, 8.5 mg/kg, 8.0 mg/kg, 7.5 mg/kg, 7.0 mg/kg, 6.5 mg/kg, 6.0 mg/kg, 5.5 mg/kg, 5.0 mg/kg, 4.5 mg/kg, 4.0 mg/kg, 3.5 mg/kg, 3.0 mg/kg, 2.5 mg/kg, 2.0 mg/kg, 1.5 mg/kg, 1.0 mg/kg, or any combination of these upper and lower limits.
Therapeutically effective doses of a small molecule CD47 blockade such as those disclosed herein also, for example, include 0.01 mg/kg to 1,000 mg/kg and any subrange or value of mg/kg therein such as 0.01 mg/kg to 500 mg/kg or 0.05 mg/kg to 500 mg/kg, or 0.5 mg/kg to 200 mg/kg, or 0.5 mg/kg to 150 mg/kg, or 1.0 mg/kg to 100 mg/kg, or 10 mg/kg to 50 mg/kg.
[02481 According to certain aspects, the anti-CD47 agent is a soluble CD47 polypeptide that specifically binds SIRPa and reduces the interaction between CD47 on one cell (e.g., an infected cell) and S1RPa on another cell (e.g., a phagocytic cell). A suitable soluble CD47 polypeptide can bind SIRPa without activating or stimulating signaling through SIRPa because activation of SIRPa would inhibit phagocytosis. Instead, suitable soluble CD47 polypeptides facilitate the preferential phagocytosis of infected cells over non-infected cells. Those cells that express higher levels of CD47 (e.g., infected cells) relative to normal, non-target cells (normal cells) will be preferentially phagocytosed. Thus, a suitable soluble CD47 polypeptide specifically binds SIRPa without activating/stimulating enough of a signaling response to inhibit phagocytosis. In some cases, a suitable soluble CD47 polypeptide can be a fusion protein (for example, as described in U.S. Pub. No. 20100239579).
[0249] Advantageously, CD47 blockade can enhance the cy-totoxic and prophagocytotic effect of a radiolabeled targeting agent, such as a radiolabeled HER3 and/or HER2 targeting agent, while reducing the dose-limiting radiotoxicity of the targeting agent, thereby improving tolerability and permitting higher radiation doses of the targeting agent to be used/tolerated in the treatment of a subject.
[0250] EXAMPLES
[0251] Example 1: Production of radiolabeled HER3 targeting agent [0252] The 1-IER3 targeting agent, such as a monoclonal antibody against 1-IER3, may be labeled with Indium-111 ("An) or Actinium-225 (125Ac) according to procedures detailed in International Publication No. WO 2017/155937 and US Provisional Patent Application No.
63/042,651 filed December 9, 2019 titled "Compositions and methods for preparation of site-specific radioconjugates.-[0253] Radiolabeling: As example, the antibody may be conjugated to a chelator-bearing linker, for example, as described herein or in the preceding patent applications. An exemplary linker includes at least dodecane tetraacetic acid (DOTA), wherein a goal of the conjugation reaction is to achieve a DOTA-antibody ratio of 3:1 to 5:1. Chelation with the radionuclide "In or 225Ac may then be performed and efficiency and purity of the resulting or 225Ac-labeled anti-HER3 antibody may be determined by HPLC and iTLC.
[0254] An exemplary labeling reaction for 225AC is as follows: A reaction including 15[11 0.15M NH40Ac buffer, pH=6.5 and 24 (101ag) DOTA-anti-HER3 (5 mg/ml) may be mixed in an Eppendorf reaction tube, and 4uL 225Ac (10 tiCi) in 0.05 M HC1 subsequently added. The contents of the tube may be mixed with a pipette tip and the reaction mixture incubated at 37 C
for 90 min with shaking at 100 rpm. At the end of the incubation period, 3 [EL
of a 1mM DTPA
solution may be added to the reaction mixture and incubated at room temperature for 20 min to bind the unreacted 225AC into the 225Ac-DTPA complex. Instant thin layer chromatography with 10cm silica gel strip and 10mM EDTA/normal saline mobile phase may be used to determine the radiochemical purity of 225Ac-DOTA-anti-HER3 through separating 225Ac-labeled anti-HER3 (225 Ac-DOTA-anti-FTER3) from free 225Ac (225Ac-DTPA). In this system, the radiolabeled antibody stays at the point of application and 225Ac-DTPA moves with the solvent front. "[he strips may be cut in halves and counted in the gamma counter equipped with the multichannel analyzer using channels 72-110 for 225Ac to exclude its daughters.
[0255] Purification: An exemplary radiolabeled HER3 targeting agent, such as 225Ac-DOTA-anti-HER3, may be purified either on PD10 columns pre-blocked with 1% HSA
or on Vivaspin centrifugal concentrators with a 50 kDa MW cut-off with 2 x 1.5 mL
washes, 3 min per spin. HPLC analyses of the 225Ac-DOTA-anti-HER3 after purification may be conducted using a Waters HPLC system equipped with flow-through Waters UV and Bioscan Radiation detectors, using a TSK3000SW XL column eluted with PBS at pH=7.4 and a flow rate of lml/min.
[0256] Stability determination: An exemplary radiolabeled HER3 targeting agent, such as 225Ac-DOTA-anti-HER3, may be used for stability determination, wherein the 225Ac-DOTA-anti-HER3 may be tested either in the original volume or diluted (2-10 fold) with the working buffer (0.15 M NI-140Ac) and incubated at room temperature (rt) for 48 hours or at 4 C for 96 hours and tested by ITLC. Stability is determined by comparison of the intact radiolabeled anti-HER3 before and after incubation. Other antibodies labeled with 225AC have been found to be stable at 4 C for up to 96 hrs.
[0257] Immunoreactivity (IR) determination: An exemplary radiolabeled HER3 targeting agent, such as 225Ac-DOTA-anti-HER3, may be used in immunoreactivity experiments. HER3 positive cells and control HER3 negative cells may be used in the amounts of 1.0-7.5 million cells per sample to investigate the amount of binding (percent radioactivity binding to cells after several washes; or using an immunoreactive fraction (IRE) bead assay may be performed according to methods disclosed in as described by Sharma, 2019) Prior assays for other antibodies radiolabeled with "In or 225Ac demonstrated about 50-60%
immunoreactivity.
[0258] EXAMPLE 2¨ Exemplary PARPi administration and dosing regimes [0259] (A) Olaparib (Lynparza ) - Normal and Reduced Dosing Regimens [0260] Olaparib is sold by Astra7eneca under the brand name Lynparza .
Lynparza is sold in tablet form at 100 mg and 150 mg. The dosage is 300 mg taken orally twice daily for a daily total of 600 mg Dosing continues until disease progression or unacceptable toxicity. This dosing regimen is referred to herein as the "normal" human dosing regimen for Lynparza , regardless of the disorder treated. Any dosing regimen having a shorter duration (e.g., 21 days) or involving the administration of less Lynparza (e.g., 300 mg/day) is referred to herein as a -reduced" human dosing regimen. Examples of reduced human dosing regimens include the following: (i) 550 mg/day; (ii) 500 mg/day; (iii) 450 mg/day; (iv) 400 mg/day;
(v) 350 mg/day;
(vi) 300 mg/day; (vii) 250 mg/day; (viii) 200 mg/day; (ix) 150 mg/day; (x) 100 mg/day; or (xi) 50 mg/day.
[0261] (B) Niraparib (Zejula ) - Normal and Reduced Dosing Regimens [0262] Niraparib is sold by Tesaro under the brand name Zejula . Zejula is sold in capsule form at 100 mg. The dosage is 300 mg taken orally once daily. Dosing continues until disease progression or unacceptable adverse reaction. This dosing regimen is referred to herein as the "normal" human dosing regimen for Zejula , regardless of the disorder treated. Any dosing regimen having a shorter duration (e.g., 21 days) or involving the administration of less Zejula (e.g., 150 mg/day) is referred to herein as a -reduced" human dosing regimen.
Examples of reduced human dosing regimens include the following: (i) 250 mg/day; (ii) 200 mg/day; (iii) 150 mg/day; (iv) 100 mg/day; or (v) 50 mg/day.
[0263] (C) Rucaparib (Rubracat) - Normal and Reduced Dosing Regimens [0264] Rucaparib is sold by Clovis Oncology, Inc. under the brand name RubracaTM.
RubracaTM is sold in tablet form at 200 mg and 300 mg. The dosage is 600 mg taken orally twice daily for a daily total of 1,200 mg. Dosing continues until disease progression or unacceptable toxicity. This dosing regimen is referred to herein as the "normal" human dosing regimen for RubracaTM, regardless of the disorder treated. Any dosing regimen having a shorter duration (e.g., 21 days) or involving the administration of less RubracaTM
(e.g., 600 mg/day) is referred to herein as a "reduced" human dosing regimen. Examples of reduced human dosing regimens include the following: (i) 1,150 mg/day; (ii) 1,100 mg/day; (iii) 1,050 mg/day; (iv) 1,000 mg/day; (v) 950 mg/day; (vi) 900 mg/day; (vii) 850 mg/day; (viii) 800 mg/day; (ix) 750 mg/day; (x) 700 mg/day; (xi) 650 mg/day; (xii) 600 mg/day; (xiii) 550 mg/day;
(xiv) 500 mg/day; (xv) 450 mg/day; (xvi) 400 mg/day; (xvii) 350 mg/day; (xviii) 300 mg/day; (xix) 250 mg/day; (xx) 200 mg/day; (xxi) 150 mg/day; or (xxii) 100 mg/day.
[0265] (D) ¨ Talazoparib (TalzennalM) - Normal and Reduced Dosing Regimens [0266] Talazoparib is sold by Pfizer Labs under the brand name TalzennaTM.
TalzennaTM is sold in capsule form at 1 mg. The dosage is 1 mg taken orally.
Dosing continues until disease progression or unacceptable toxicity. This dosing regimen is referred to herein as the "normal" human dosing regimen for TalzennaTM, regardless of the disorder treated. Any dosing regimen having a shorter duration (e.g., 21 days) or involving the administration of less TalzennaTM (e.g., 0.5 mg/day) is referred to herein as a "reduced" human dosing regimen.
Examples of reduced human dosing regimens include the following: (i) 0.9 mg/day; (ii) 0.8 mg/day; (iii) 0.7 mg/day; (iv) 0.6 mg/day; (v) 0.5 mg/day; (vi) 0.4 mg/day;
(vii) 0.3 mg/day;
(viii) 0.2 mg/day; or (ix) 0.1 mg/day.
[0267] EXAMPLE 3: Dosing regimens for HER3 targeting agent and PARPi [0268] A human patient may be treated according to the following regimen. One of olaparib, niraparib, rucaparib or talazoparib (PARPi) is orally administered according to one of the dosing regimens listed in Example 2, accompanied by intravenous administration of a radiolabeled 1-1ER3 targeting agent as detailed herein in either single or fractional administration.
For example, the dosing regimens include, by way of example: (a) the PARPi and the 1-IER3 targeting agent administered concurrently, wherein (i) each is administered beginning on the same day, (ii) the HER3 targeting agent is administered in a single dose or fractionated doses not less than one week apart, and (iii) the PARPi is administered daily or twice daily (as appropriate), and for a duration equal to or exceeding that of the HER3 targeting agent administration; or (b) the PARPi and HER3 targeting agent are administered concurrently, wherein (i) the PARPi administration precedes HER3 targeting agent administration by at least one week, (ii) the HER3 targeting agent is administered in a single dose or fractionated doses not less than one week apart, and (iii) the PARPi is administered daily or twice daily (as appropriate), and for a duration equal to or exceeding that of the HER3 targeting agent administration.
[0269] EXAMPLE 4: Dosing regimens for HER3 targeting agent and a CD47 Blockade.
[0270] According to certain aspects of the present invention, the CD47 blocking agent may, for example, be a monoclonal antibody that prevents CD47 binding to SlRPa. Exemplary protein CD47 blockades include magrolimab, lemzoparlimab, A0-176, TTI-621, TTI-622, or a combination thereof. The CD47 blockade may alternatively, or additionally, include agents that modulate the expression of CD47 and/or SIRPa, such as phosphorodiamidate morpholino oligomers (PMO) that block translation of CD47 such as MBT-001 (PMO, morpholino, Sequence: 5'-CGTCACAGGCAGGACCCACTGCCCA-3) [SEQ ID NO:114]) or any of the PMO oligomer CD47 inhibitors disclosed in any of U.S. Patent No. 8,557,788, US, Patent No.
8,236,313, U.S. Patent No. 10,370,439 and lnt'l Pub. No. W02008060785.
'therapeutically effective doses of anti-CD47 antibodies include at least 0.05 ¨ 10 mg/kg Thus, methods of the present invention may include administering one or more of the anti-CD47 antibodies or other agents, accompanied by intravenous administration of a radiolabeled HER3 targeting agent as detailed herein in either single or fractional administration. For example, the dosing regimens include, by way of example: (a) the anti-CD47 antibody or agent and the 1-IE,R3 targeting agent administered concurrently, wherein (i) each is administered beginning on the same day, (ii) the HER3 targeting agent is administered in a single dose or fractionated doses not less than one week apart, and (iii) the anti-CD47 antibody or agent is administered daily or twice daily (as appropriate), and for a duration equal to or exceeding that of the HER3 targeting agent administration; or (b) the anti-CD47 antibody or agent and HER3 targeting agent are administered concurrently, wherein (i) the anti-CD47 antibody or agent administration precedes HER3 targeting agent administration by at least one week, (ii) the HER3 targeting agent is administered in a single dose or fractionated doses not less than one week apart, and (iii) the anti-CD47 antibody or agent is administered daily or twice daily (as appropriate), and for a duration equal to or exceeding that of the HER3 targeting agent administration.
[0271] EXAMPLES: Dosing regimens for HER3 targeting agent and an ICI.
[0272] According to certain aspects of the present invention, the immune checkpoint inhibitor (ICI) may be a monoclonal antibody against any of PD-1, PD-L1, PD-L2, CTLA-4, CD137. Therapeutically effective doses of these antibodies include at least 0.05 ¨ 10 mg/kg.
Thus, method of the present invention include administering one or more ICI, accompanied by intravenous administration of a radiolabeled HER3 targeting agent as detailed herein in either single or fractional administration. For example, the dosing regimens include, by way of example: (a) the ICI and the HER3 targeting agent administered concurrently, wherein (i) each is administered beginning on the same day, (ii) the HER3 targeting agent is administered in a single dose or fractionated doses not less than one week apart, and (iii) the ICI is administered daily or twice daily (as appropriate), and for a duration equal to or exceeding that of the HER3 targeting agent administration; or (b) the ICI and HER3 targeting agent are administered concurrently, wherein (i) the anti-CD47 antibody administration precedes HER3 targeting agent administration by at least one week, (ii) the HER3 targeting agent is administered in a single dose or fractionated doses not less than one week apart, and (iii) the ICI is administered daily or twice daily (as appropriate), and for a duration equal to or exceeding that of the 1-IER3 targeting agent administration, [0273] Without limitation, the following aspects are also provided by this disclosure:
[0274] Aspect 1. A method for treating a solid cancer in a mammalian subject such as a human patient, the method including: administering to the subject a therapeutically effective amount of a radiolabeled HER3 targeting agent.
[0275] Aspect 2. The method according to any preceding aspect, wherein the solid cancer is a breast cancer, gastric cancer, bladder cancer, cervical cancer, endometrial cancer, skin cancer, stomach cancer, testicular cancer, esophageal cancer, bronchioloalveolar cancer, prostate cancer, colorectal cancer, ovarian cancer, cervical epidermoid cancer, pancreatic cancer, lung cancer, renal cancer, head and neck cancer, or any combination thereof [0276] Aspect 3. The method according to any preceding aspect, wherein the solid cancer is colorectal cancer, gastric cancer, ovarian cancer, non-small cell lung carcinoma, head and neck squamous cell cancer, pancreatic cancer, renal cancer, or any combination thereof.
[0277] Aspect 4. The method according to any preceding aspect, wherein the solid cancer is a HER3-positive cancer such as a 1-lER3-positive solid tumor.
[0278] Aspect 5. The method according to any preceding aspect, wherein the radiolabeled HER3 targeting agent includes a radiolabel selected from 13115 12515 12315 90y5 177Lu5 186Re5 188Re5 89sr, 153sm5 32p5 225Ac5 213Bi5 213p05 211At5 212Bi5 213Bi5 223Ra5 227Th, 149Tb5 137cs, 212=s+ 5 YID 1 3Pd, or any of those disclosed herein, or any combination thereof.
[0279] Aspect 6. The method according to any preceding aspect, wherein the radiolabeled HER3 targeting agent includes a radiolabel selected from 1-31I
90Y, 177Lu, 225Ac, 213Bi, 211A.t, 213Bi, 227Th, 212Pb, or any combination thereof.
[0280] Aspect 7. The method according to any preceding aspect, wherein the radiolabeled HER3 targeting agent includes an antibody against HER3.
[0281] Aspect 8. The method according to any preceding aspect, wherein the targeting agent includes an anti-HER3 monoclonal antibody such as any of those disclosed herein, such as a HER3 antibody selected from Patritumab, Seribantumab (MM-121), Lumretuzumab, Elgemtumab, GSK2849330, and AV-203 and any combination thereof.
[0282] Aspect 9. The method according to any preceding aspect, wherein the targeting agent includes a monoclonal antibody: (i) having a heavy chain sequence including SEQ ID NO:77 and/or a light chain sequence including SEQ ID NO:78; (ii) having an immunoglobulin heavy chain variable region including a CDR-H1 including SEQ ID
NO:15, a CDR-H2 including SEQ ID NO:16, and/or a CDR-H3 including SEQ ID NO:17, and/or an immunoglobulin light chain variable region including a CDR-L1 including SEQ ID
NO:18, a CDR-L2 including SEQ ID NO:19, and/or a CDR-L3 including SEQ ID NO:20; (iii) having an immunoglobulin heavy chain variable region including SEQ ID NO:21 and/or an immunoglobulin light chain variable region including SEQ ID NO:22; or (iv) having an immunoglobulin heavy chain amino acid sequence of SEQ ID NO:23 and/or an immunoglobulin light chain amino acid sequence of SEQ ID NO:24.
[0283] Aspect 10. The method according to any preceding aspect, wherein the targeting agent includes a monoclonal antibody including a heavy chain variable region having an amino acid sequence as set forth in SEQ. ID NO:7 and/or a light chain variable region having an amino acid sequence as set forth in SEQ. ID NO:8.
[0284] Aspect 11. The method according to any preceding aspect, wherein the targeting agent includes a monoclonal antibody including one or more of the heavy chain N-terminal region and complementarity determining regions (CDRs) having amino acid sequences as set forth in SEQ. ID NO:13 and/or 1-3, respectively; and/or including one or more of the light chain N-terminal region and CDRs having amino acid sequences as set forth in SEQ. ID NO:14 and/or 4-6, respectively.
[02851 Aspect 12. The method according to any preceding aspect, wherein the effective amount of the radiolabeled HER3 targeting agent is a maximum tolerated dose.
[02861 Aspect 13. The method according to any preceding aspect, wherein the radiolabeled HER3 targeting agent is 225A 177LU-, or 1311-labeled.
[02871 Aspect 14. The method according to any preceding aspect, wherein the therapeutically effective amount of the radiolabeled HER3 targeting agent includes a single dose that delivers less than 2Gy, or less than 8 Gy, such as doses of 2 Gy to 8 Gy, to the subject.
[02881 Aspect 15. The method according to any preceding aspect, wherein the radiolabeled HER3 targeting agent is 'Ac-labeled, and the effective amount of the 'Ac-labeled HER3 targeting agent includes a dose of 0.1 to 50 uCi/kg body weight of the subject, or 0.2 to 20 uCi/kg body weight of the subject, or 0.5 to 10 uCi/kg subject body weight.
[02891 Aspect 16. The method according to any preceding aspect, wherein the radiolabeled HER3 targeting agent is a full-length antibody against HER3 that is 225Ac-labeled, and the effective of the 'Ac-labeled HER3 targeting agent includes less than 5 uCi/kg body weight of the subject, such as 0.1 to 5 uCi/kg body weight of the subject.
[02901 Aspect 17. The method according to any one of aspects 1 to 6, wherein the radiolabeled HER3 targeting agent is an antibody fragment, such as a minibody or nanobody against HER3 that is 'Ac-labeled, and the effective of the 'Ac-labeled HER3 targeting agent includes greater than 5 uCi/kg body weight of the subject, such as 5 to 20 uCi/kg body weight of the subject.
[0291] Aspect 18. The method according to any one of aspects 1 to 14, wherein the radiolabeled HER3 targeting agent is 225Ac-labeled, and the effective amount of the l'Ac-labeled HER3 targeting agent includes 2 ILICi to 2mCi, or 2 LICi to 250 [iCi, or 75 tCi to 400 pCi.
[0292] Aspect 19. The method according to any one of aspects 1 to 14, wherein the radioisotope labeled HER3 targeting agent is 177Lu-labeled and the effective amount of the EIER3 targeting agent includes a dose of less than 1000 uCi/kg body weight of the subject, such as a dose of 1 to 900 uCi/kg body weight of the subject, or 5 to 250 uCi/kg body weight of the subject or 50 to 450 uCi/kg body weight.
[02931 Aspect 20. The method according to any one of aspects 1 to 14, wherein the radioisotope labeled HER3 targeting agent is 177Lu-labeled, and the effective amount of the '77Lu-labeled HER3 targeting agent includes a dose of 10 mCi to at or below 30 mCi, or from at least 100 pCi to at or below 3 mCi, or from 3 mCi to at or below 30 mCi.
[0294] Aspect 21. The method according to any one of aspects 1 to 14, wherein the radiolabeled HER3 targeting agent is 131I-labeled, and the effective amount of the 131I-labeled HER3 targeting agent includes a dose of less than 1200 mCi, such as a dose of 25 to 1200 mCi, or 100 to 400 mCi, or 300 to 600 mCi, or 500 to 1000 mCi.
[0295] Aspect 22. The method according to any one of aspects 1 to 14, wherein the radiolabeled HER3 targeting agent is 131I-labeled, and the effective amount of the 131I-labeled fIER3 targeting agent includes a dose of less than 200 mCi, such as a dose of 1 to 200 mCi, or 25 to 175 mCi, or 50 to 150 mCi.
10296] Aspect 23. The method according to any preceding aspect, wherein the effective amount of the HER3 targeting agent includes a protein dose of less than 3 mg/kg body weight of the subject, such as from 0.001 mg/kg patient weight to 3.0 mg/kg patient weight, or from 0.005 mg/kg patient weight to 2.0 mg/kg patient weight, or from 0.01 mg/kg patient weight to 1 mg/kg patient weight, or from 0.1 mg/kg patient weight to 0.6 mg/kg patient weight, or 0.3 mg/kg patient weight, or 0.4 mg/kg patient weight, or 0.5 mg/kg patient weight, or 0.6 mg/kg patient weight [0297] Aspect 24. The method according to any preceding aspect, wherein the targeting agent is administered according to a dosing schedule selected from the group consisting of once every 7, 10, 12, 14, 20, 24, 28, 36, and 42 days throughout a treatment period, wherein the treatment period includes at least two doses.
[0298] Aspect 25. The method according to any one of aspects 1 to 6, wherein the HER3 targeting agent is a peptide or small molecule.
[0299] Aspect 26. The method according to any preceding aspect, further including administering to the subject a therapeutically effective amount of an immune checkpoint therapy, a chemotherapeutic agent, a DNA damage response inhibitor (DDRi), a CD47 blockade, or a combination thereof.
[0300] Aspect 27. The method according to aspect 26, wherein the immune checkpoint therapy includes an antibody or other blocking agent against CTLA-4, PD-1, TIM-3, VISTA, BTLA, LAG-3, TIGIT, CD28, 0X40, GITR, CD137, CD40, CD4OL, CD27, HVEM, PD-L1, PD-L2, PD-L3, PD-L4, CD80, CD86, CD137-L, GITR-L, CD226, B7-H3, B7-H4, BTLA, TIGIT, GALS, K1R, 2B4, CD160, or CGEN-15049, or any combination of such antibodies and blocking agents.
[0301] Aspect 28. The method according to aspect 27, wherein the immune checkpoint therapy includes an antibody against PD-1, PD-L1, PD-L2, CTLA-4, CD137, or a combination thereof.
[0302] Aspect 29. The method according to aspect 26, wherein the DDRi includes a poly(ADP-ribose) polymerase inhibitor (PARPi), an ataxia telangiectasia mutated inhibitor (ATMi), an ataxia talangiectasia mutated and Rad-3 related inhibitor (ATRi), or a Weel inhibitor.
[0303] Aspect 30. The method according to aspect 29, wherein the PARPi includes one or more of olaparib, niraparib, rucaparib and talazoparib.
[0304] Aspect 31. The method according to aspect 29, wherein the ATMi includes one or more of KU-55933, KU-59403, wortmannin, CP466722, or KU-60019.
[0305] Aspect 32. The method according to aspect 29, wherein the ATRi includes one or more of Schisandrin B, NU6027, NVP-BEA235, VE-821, VE-822, AZ20, or AZD6738.
[0306] Aspect 33. The method according to aspect 29, wherein the Weel inhibitor includes AZD-1775 (i.e., adavosertib).
[0307] Aspect 34. The method according to aspect 26, wherein the CD47 blockade includes an agent, such as a monoclonal antibody that prevents CD47 binding to S1RPa and/or an agent that modulates CD47 expression.
[0308] Aspect 35: The method according to aspect 34, wherein the CD47 blockade includes one or more of magrolimab, lemzoparlimab, A0-176, TTI-621, TTI-622, or a combination thereof; and/or wherein the agent that modulates CD47 expression includes phosphorodiamidate morpholino oligomers (PMO) that reduce expression of CD47 (e.g., MET-001).
[0309] Aspect 36: The method according to aspect 34, wherein the therapeutically effective amount of the CD47 blockade includes 0.05 to 5 mg/Kg patient weight [0310] Aspect 37. The method according to aspect 26, wherein the HER3 targeting agent is administered at least one week before the immune checkpoint therapy and/or the DDRi and/or the CD47 blockade; or wherein the immune checkpoint therapy and/or the DDRi and/or CD47 blockade is administered at least one week before the HER3 targeting agent.
[0311] Aspect 38. The method according to aspect 26, wherein the HER3 targeting agent is administered with one of the immune checkpoint therapy or the DDRi or the CD47 blockade, and the other of the immune checkpoint therapy or the DDRi or the CD47 blockade is administered either before or after the HER3 targeting agent.
[0312] Aspect 39. The method according to aspect 26, wherein the HER3 targeting agent is administered simultaneously with the immune checkpoint therapy and/or the DDRi and/or the CD47 blockade.
[0313] Aspect 40. The method according to any preceding aspect, wherein the targeting agent is a multi-specific antibody, wherein the multi-specific antibody includes: a first target recognition component which specifically binds to an epitope of HER3, and a second target recognition component which specifically binds to a different epitope of 1-LER3 than the first target recognition component, or an epitope of a different antigen.
[0314] Aspect 41. The method according to aspect 40, wherein the HER3 targeting agent includes a bispecific antibody against FIER3/HER2 such as MM-111 or MCLAO-128, or against IGF-1R/HER3 such as MM-141 (i.e., Istiratumab), and/or against HER1/HER3 such as MEHD7945A (i.e., Duligotumab).
[0315] Aspect 42. A method for treating a proliferative disease or disorder, the method including: diagnosing the subject with HER3-positive cells; and if the subject has HER3-positive cells, administering to the subject a therapeutically effective amount of an HER3 targeting agent according to any of the methods of aspects 1 to 41.
[0316] Aspect 43. The method according to aspect 42, wherein the diagnosing includes obtaining a sample of blood or tissue from the subject; mounting the sample on a substrate; and detecting the presence or absence of HER3 antigen using a diagnostic antibody, wherein the diagnostic antibody includes an antibody against HER3 labeled with a radiolabel such as 3H, 14c, 3213, 35S, and 12571; fluorescent or chemiluminescent compounds, such as fluorescein isothiocyanate, rhodamine, or luciferin; or an enzyme, such as alkaline phosphatase, 3-gal actosidase, or horseradish peroxidase.
[0317] Aspect 44. The method according to aspect 42, wherein the diagnosing includes administering a HER3 targeting agent to the subject, wherein the HER3 targeting agent includes isF, , a radiolabel selected from the group including 6sGa, 64cu , g9zr, , 124- 99mTc, or 111In;
waiting a time sufficient to allow the HER3 targeting agent to accumulate at a tissue site, and imaging the tissues with a non-invasive imaging technique to detect presence or absence of HER3-positive cells.
[0318] Aspect 45. The method according to aspect 44, wherein the non-invasive imaging technique includes positron emission tomography (PET imaging) for isF, tic, 68,6a, 64cu, 89Zr, or 124I labeled HER3 targeting agents or single photon emission computed tomography (SPECT
imaging) for 99"1Tc or 111-In labeled HER3 targeting agents.
[0319] While various specific embodiments have been illustrated and described herein, it will be appreciated that various changes can be made without departing from the spirit and scope of the invention(s). Moreover, features described in connection with one aspect of the invention may be used in conjunction with other aspects of the invention, even if not explicitly exemplified in combination within.
[0320] References [0321] Mishra R, Patel H, Alanazi S, Yuan L, Garrett JT. HER3 signaling and targeted therapy in cancer. Oncol Rev. 2018;12(1).
[0322] Meneses-Lorente G, Friess T, Kolm I, et al. Preclinical pharmacokinetics, pharmacodynamics, and efficacy of RG7116: a novel humanized, glycoengineered anti-1-IER3 antibody. Cancer Chemother Pharmacol. 2015;75(4):837-850.
[0323] Mirschberger C, Schiller CB, Schraml M, et al. RG7116, a Therapeutic Antibody That Binds the Inactive HER3 Receptor and Is Optimized for Immune Effector Activation.
Cancer Res. 2013;73(16):5183-5194.
[0324] Meulendijks D, Jacob W, Martinez-Garcia M, et al. First-in-Human Phase 1 Study of Lumretuzumab, a Glycoengineered Humanized Anti-HER3 Monoclonal Antibody, in Patients with Metastatic or Advanced HER3-Positive Solid Tumors. Clin Cancer Res.
2016;22(4):877-885.
[0325] Reynolds KL, Bedard PL, Lee S-H, et al. A phase I open-label dose-escalation study of the anti-FIER3 monoclonal antibody LJM716 in patients with advanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer.
BMC Cancer. 2017;17(1):646.
Claims (29)
1. A method for treating a solid cancer in a mammalian subject, the method comprising:
administering to the subject a therapeutically effective amount of a radionuclide labeled HER3 targeting agent.
administering to the subject a therapeutically effective amount of a radionuclide labeled HER3 targeting agent.
2. The method of Claim 1, wherein the radionuclide labeled HER3 targeting agent 1251, 1231, 90y, 177Lu, 186- e, 188Re, 89Sr, 153Srn, comprises a radiolabel selected from 1311, K
32p, 225Ao, 213Bi, 213po, 211At, 212Bi, 213Bi, 223Ra, 227Th, 149Tb, 137C s, 212pb or law, or a combination thereof.
32p, 225Ao, 213Bi, 213po, 211At, 212Bi, 213Bi, 223Ra, 227Th, 149Tb, 137C s, 212pb or law, or a combination thereof.
3. The method of Claim 1, wherein the radionuclide labeled HER3 targeting agent comprises a radiolabel selected from 225Ao, 177Lu, 1311, 90y, 213Bi, 211m, 213Bi, 227Th, 212Pb, or a combination thereof.
4. The method of Claim 1, wherein the radionuclide labeled HER3 targeting agent comprises a humanized antibody against HER3.
5. lhe method of claim 1, wherein the radionuclide labeled HER3 targeting agent comprises one or more of patritumab, seribantumab, lumretuzumab, elgemtumab, AV203, GSK2849330.
6. The method of Claim 1, wherein the radionuclide labeled I-1ER3 targeting agent comprises a monoclonal antibody comprising one or both of a heavy chain sequence comprising SEQ ID NO:77 and a light chain sequence comprising SEQ ID NO:78.
7. The method of Claim 1, wherein the radionuclide labeled HER3 targeting agent comprises a monoclonal antibody comprising:
(i) one or both of (a) an immunoglobulin heavy chain variable region including a CDR-H1 including SEQ ID NO:15, a CDR-H2 including SEQ ID NO:16, and/or a CDR-H3 including SEQ ID NO:17, and (b) an immunoglobulin light chain variable region including a CDR-L1 including SEQ ID NO:18, a CDR-L2 including SEQ ID NO:19, and/or a CDR-L3 including SEQ ID NO:20, (ii) one or both of an immunoglobulin heavy chain variable region including SEQ
ID NO:21 and an immunoglobulin light chain variable region including SEQ ID
NO:22;
or (iii) one or both of an immunoglobulin heavy chain amino acid sequence of SEQ
ID NO.23 and an immunoglobulin light chain amino acid sequence of SEQ ID
NO.24.
(i) one or both of (a) an immunoglobulin heavy chain variable region including a CDR-H1 including SEQ ID NO:15, a CDR-H2 including SEQ ID NO:16, and/or a CDR-H3 including SEQ ID NO:17, and (b) an immunoglobulin light chain variable region including a CDR-L1 including SEQ ID NO:18, a CDR-L2 including SEQ ID NO:19, and/or a CDR-L3 including SEQ ID NO:20, (ii) one or both of an immunoglobulin heavy chain variable region including SEQ
ID NO:21 and an immunoglobulin light chain variable region including SEQ ID
NO:22;
or (iii) one or both of an immunoglobulin heavy chain amino acid sequence of SEQ
ID NO.23 and an immunoglobulin light chain amino acid sequence of SEQ ID
NO.24.
8. The method of Claim 1, wherein the radionuclide labeled HER3 targeting agent is a monoclonal antibody comprising a heavy chain having complementarity determining regions (CDRs) having amino acid sequences as set forth in SEQ. ID NO:13 and/or 1-3, respectively; and/or a light chain having CDRs having amino acid sequences as set forth in SEQ. ID NO:14 and/or 4-6, respectively.
9. The method of Claim 1, wherein the solid cancer is a breast cancer, gastric cancer, bladder cancer, cervical cancer, endometrial cancer, skin cancer, stomach cancer, testicular cancer, esophageal cancer, bronchioloalveolar cancer, prostate cancer, colorectal cancer, ovarian cancer, cervical epidermoid cancer, pancreatic cancer, lung cancer, renal cancer, head and neck cancer, or any combination thereof.
10. The method of Claim 1, wherein the solid cancer is breast cancer, gastric cancer, pancreatic cancer, or any combination thereof.
1 1. The method of Claim 1, wherein the solid cancer comprises HER3-positive cancer cells.
12. The method of Claim 1, wherein the effective amount of the radionuclide labeled HER3 targeting agent is a maximum tolerated dose.
13. The method of Claim 1, wherein the radionuclide labeled HER3 targeting agent is 225Ac-labeled, and the effective amount of the 225Ac-labeled HER3 targeting agent comprises a dose of 0.1 to 50 uCi/kg body weight of the subject, or 0.1 to 5 uCi/kg body weight of the subject, or 5 to 20 uCi/kg subject body weight.
14. The method of Claim 1, wherein the radionuclide labeled FIER3 targeting agent is 225AC-labeled, and the effective amount of the 225Ac-labeled 11ER3 targeting agent comprises a dose of 2 uCi to 2mCi, or 2 uCi to 250 uCi, or 75 uCi to 400 p.Ci.
15. The method of Claim 1, wherein the effective amount of the radionuclide labeled HER3 targeting agent comprises a protein dose of less than 3 mg/kg body weight of the subject, such as from 0.001 mg/kg patient weight to 3.0 mg/kg patient weight, or from 0.005 mg/kg patient weight to 2.0 mg/kg patient weight, or from 0.01 mg/kg patient weight to 1 mg/kg patient weight, or from 0.1 mg/kg patient weight to 0.6 mg/kg patient weight, or 0.3 mg/kg patient weight, or 0.4 mg/kg patient weight, or 0.5 mg/kg patient weight, or 0.6 mg/kg patient weight.
16. The method of Claim 1, wherein the radionuclide labeled BER3 targeting agent is administered according to a dosing schedule selected from the group consisting of once every 7, 10, 12, 14, 20, 24, 28, 36, and 42 days throughout a treatment period, wherein the treatment period includes at least two doses.
17. The method of Claim 1, further comprising:
administering to the subject a therapeutically effective amount of an immune checkpoint therapy, a DNA damage response inhibitor (DDRi), a CD47 blockade, a chemotherapeutic agent, or a combination thereof.
administering to the subject a therapeutically effective amount of an immune checkpoint therapy, a DNA damage response inhibitor (DDRi), a CD47 blockade, a chemotherapeutic agent, or a combination thereof.
18. The method of Claim 17, wherein the immune checkpoint therapy comprises an antibody against PD-1, PD-L1, PD-L2, CTLA-4, CD137, or a combination thereof
19. The method of Claim 17, wherein the DDRi comprises a poly(ADP-ribose) polymerase inhibitor (PARPi), an ataxia telangiectasia mutated inhibitor (ATMi), an ataxia talangiectasia mutated and Rad-3 related inhibitor (ATRi), or a Weel inhibitor.
20. The method of Claim 17, wherein the CD47 blockade comprises one or more of magrolimab, lemzoparlimab, A0-176, TTI-621, TTI-622, and a CD47 expression-modulating agent.
21. The method of Claim 17, wherein the CD47 blockade comprises a CD47 expression-modulating agent.
22. The method of Claim 21, wherein the CD47 expression-modulating agent is IVIBT-001.
23. The method of Claim 1, wherein the radionuclide labeled HER3 targeting agent is also specific for HER2.
24. The method of Claim 1 or 23, wherein the radiolabeled I1ER3 targeted agent comprises a chemically conjugated chelator group that chelates a radionuclide.
25. The method of Claim 24, wherein the chelator group comprises DOTA.
26. The method of any one of the preceding claims, wherein the administering step comprises:
administering to the subject a therapeutically effective amount of a therapeutic composition comprising a radiolabeled fraction of the HER3 targeting agent and a non-radiolabeled fraction of the HER3 targeting agent.
administering to the subject a therapeutically effective amount of a therapeutic composition comprising a radiolabeled fraction of the HER3 targeting agent and a non-radiolabeled fraction of the HER3 targeting agent.
27. The method of Claim 26, wherein the therapeutic composition further comprises at least one pharmaceutically acceptable excipient.
28. The method of any one of the preceding claims, further comprising the step of:
diagnosing the subject with HER3-positive cancer prior to the administering step.
diagnosing the subject with HER3-positive cancer prior to the administering step.
29. The method of Claim 28, wherein the diagnosing step comprises imaging HER3-positive cells in the subject using a radionuclide labeled HER3 targeting agent.
3 0. The method of claim 29, wherein the same HER3 targeting agent is used for the diagnosing step and the administering step.
3 1. The method of Claim 30, wherein the HER3 targeting agent is labeled with a different radionuclide in the diagnosing step as in the administering step.
3 0. The method of claim 29, wherein the same HER3 targeting agent is used for the diagnosing step and the administering step.
3 1. The method of Claim 30, wherein the HER3 targeting agent is labeled with a different radionuclide in the diagnosing step as in the administering step.
Applications Claiming Priority (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202063116225P | 2020-11-20 | 2020-11-20 | |
US63/116,225 | 2020-11-20 | ||
US202063118181P | 2020-11-25 | 2020-11-25 | |
US63/118,181 | 2020-11-25 | ||
US202163226699P | 2021-07-28 | 2021-07-28 | |
US63/226,699 | 2021-07-28 | ||
US202163250725P | 2021-09-30 | 2021-09-30 | |
US63/250,725 | 2021-09-30 | ||
USPCT/US2021/056259 | 2021-10-22 | ||
PCT/US2021/056259 WO2022087416A1 (en) | 2020-10-22 | 2021-10-22 | Combination radioimmunotherapy and cd47 blockade in the treatment of cancer |
PCT/US2021/060370 WO2022109404A1 (en) | 2020-11-20 | 2021-11-22 | Her3 radioimmunotherapy for the treatment of solid cancers |
Publications (1)
Publication Number | Publication Date |
---|---|
CA3199259A1 true CA3199259A1 (en) | 2022-05-27 |
Family
ID=81709768
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA3199259A Pending CA3199259A1 (en) | 2020-11-20 | 2021-11-22 | Her3 radioimmunotherapy for the treatment of solid cancers |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP4247430A1 (en) |
JP (1) | JP2023550462A (en) |
KR (1) | KR20230128271A (en) |
AU (1) | AU2021382717A1 (en) |
CA (1) | CA3199259A1 (en) |
IL (1) | IL303030A (en) |
MX (1) | MX2023005940A (en) |
WO (1) | WO2022109404A1 (en) |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2991799A1 (en) * | 2015-07-15 | 2017-01-19 | Zymeworks Inc. | Drug-conjugated bi-specific antigen-binding constructs |
CA3123873A1 (en) * | 2018-12-21 | 2020-06-25 | Actinium Pharmaceuticals, Inc. | Combination radioimmunotherapy and immune checkpoint therapy in the treatment of cancer |
-
2021
- 2021-11-22 AU AU2021382717A patent/AU2021382717A1/en active Pending
- 2021-11-22 JP JP2023530591A patent/JP2023550462A/en active Pending
- 2021-11-22 KR KR1020237020749A patent/KR20230128271A/en unknown
- 2021-11-22 IL IL303030A patent/IL303030A/en unknown
- 2021-11-22 WO PCT/US2021/060370 patent/WO2022109404A1/en active Application Filing
- 2021-11-22 MX MX2023005940A patent/MX2023005940A/en unknown
- 2021-11-22 CA CA3199259A patent/CA3199259A1/en active Pending
- 2021-11-22 EP EP21895766.0A patent/EP4247430A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
EP4247430A1 (en) | 2023-09-27 |
JP2023550462A (en) | 2023-12-01 |
MX2023005940A (en) | 2023-07-27 |
AU2021382717A1 (en) | 2023-07-06 |
WO2022109404A1 (en) | 2022-05-27 |
KR20230128271A (en) | 2023-09-04 |
IL303030A (en) | 2023-07-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20210220472A1 (en) | Antibodies specific to human t-cell immunoglobulin and itim domain (tigit) | |
US20220211886A1 (en) | Combination radioimmunotherapy and cd47 blockade in the treatment of cancer | |
US20240197931A1 (en) | Radioimmunotherapy directed to ccr8 for depletion of tumor infiltrating regulatory t cells | |
US20220288244A1 (en) | Combination radioimmunotherapy and cd47 blockade in the treatment of cancer | |
WO2022235676A1 (en) | Radioimmunoconjugates directed to nkg2d ligands for the treatment of cancer | |
US20220143228A1 (en) | Her3 radioimmunotherapy for the treatment of solid cancers | |
US20230092668A1 (en) | Radioconjugates targeting cd33 in the treatment of cancers | |
WO2023028613A2 (en) | Radioimmunoconjugates targeting phosphatidylserine for use in the treatment of cancer | |
US20230302168A1 (en) | Dr5 radioimmunotherapy in the treatment of solid cancers | |
US20230248855A1 (en) | Her3 radioimmunotherapy for the treatment of solid cancers | |
CA3199259A1 (en) | Her3 radioimmunotherapy for the treatment of solid cancers | |
WO2024138019A1 (en) | Her3 radioimmunotherapy for the treatment of solid cancers | |
US20240226345A1 (en) | Radioimmunoconjugates targeting calreticulin for use in the treatment of cancer | |
US20230302167A1 (en) | Radioconjugates targeting cd33 in the treatment of cancers | |
US20220251239A1 (en) | Combination radioimmunotherapy and cd47 blockade in the treatment of cancer | |
WO2022056354A1 (en) | Trophoblast glycoprotein radioimmunotherapy for the treatment of solid cancers | |
CA3233537A1 (en) | Radioimmunoconjugates targeting grp78 for use in the treatment of cancer | |
CA3228080A1 (en) | Radioconjugates targeting cd33 in the treatment of cancers | |
JP2024528081A (en) | Combination of radioimmunotherapy and CD47 blocking agents in the treatment of cancer - Patents.com |