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  • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
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  • 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
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  • A61K51/1075—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 the antibody being against an enzyme
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  • 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
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  • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
  • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
  • C07D237/30—Phthalazines
  • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
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  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
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  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
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  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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  • C07K16/2851—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72
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  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2863—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
• • C—CHEMISTRY; METALLURGY
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Definitions

• DNA single stranded breaks and double stranded breaks occur for a variety of reasons, including the presence of mutations in the pathways that include the BRCA, PTEN and ATR proteins. Such DNA breaks are repaired through multiple pathways.
• PARP inhibition results in an accumulation of single and/or double stranded breaks.
• Existing PARP inhibitors act through both inhibitors of PARP enzyme inhibition activity and through the trapping of PARP proteins inside of chromatin (“DNA- trapping”). Tumor cells with BRCA and/or PTEN mutations are sensitive to PARPi’s, while ATR inhibition (ATRi) results in a failure to repair double stranded breaks— and therefore results in the accumulation of double stranded breaks.
• An increase in single or double stranded DNA breaks results in increased cell death.
• DDRis DNA Damage Repair inhibitors
• the present disclosure encompasses the insight that combining inhibition of DNA damage repair mechanisms with a therapy that targets DNA breaks to cancer cells may provide a less toxic therapy with improved efficacy.
• Radioactive decay can cause direct physical damage (such as single or double- stranded DNA breaks) or indirect damage (such as by-stander or crossfire effects) to the biomolecules that constitute a cell.
• the present disclosure combines radioimmunoconjugates targeted to cancer cells with DNA damage repair inhibition to treat or ameliorate cancer.
• methods for treating or ameliorating cancer comprising: (i) administering to a mammal a radioimmunoconjugate, wherein the mammal has received or is receiving a DNA damage response inhibitor (DDRi); (ii) administering to a mammal a DDRi, wherein the mammal has received or is receiving a radioimmunoconjugate; or (iii) administering to the mammal a DDRi at the same time as administering the mammal a radioimmunoconjugate.
• DDRi DNA damage response inhibitor
• said method comprises administering to a mammal a DDRi, wherein the mammal has received or is receiving a radioimmunoconjugate.
• the DDRi is administered in a lower effective dose.
• the radioimmunoconjugate is administered in a lower effective dose.
• both the DDRi and the radioimmunoconjugate are administered in lower effective doses.
• the radioimmunoconjugate comprises (i) a targeting moiety, (ii) a linker, and (iii) a chelating moiety or a metal complex of a chelating moiety.
• the targeting moiety is capable of binding to a tumor-associated antigen.
• the tumor-associated antigen is a tumor-specific antigen.
• the targeting moiety is an antibody or an antigen-binding fragment thereof.
• the antibody or antigen-binding fragment thereof is an IGF1 -R antibody or an antigen-binding fragment thereof.
• the antibody or antigen-binding fragment thereof is an endosialin (TEM-1) antibody or an antigen-binding fragment thereof.
• the radioimmunoconjugate comprises a metal complex of a chelating moiety.
• the metal complex comprises a radionuclide.
• the radionuclide is an alpha emitter, e.g., an alpha emitter selected from the group consisting of Astatine-21 1 ( 211 At) , Bismuth-212 ( 212 Bi), Bismuth-213 ( 213 Bi), Actinium-225 ( 225 Ac), Radium-223 ( 223 Ra), Lead-212 ( 212 Pb), Thorium-227 ( 227 Th), and Terbium-149 ( 149 Tb).
• the radionuclide is 225 Ac.
• the radioimmunoconjugate comprises the following structure:
• the DDRi is a PARP inhibitor.
• the PARP inhibitor is a small molecule PARP inhibitor, e.g., a PARP inhibitor selected from the group consisting of niparib, niraparib, olaparib, talazoparib, pamiparib, rucaparib (camsylate), and veliparib, or an analog thereof.
• the small molecule PARP inhibitor is olaparib or an analog thereof.
• the DDRi is an ATR inhibitor.
• the ATR inhibitor is a small molecule ATR inhibitor, e.g., an ATR inhibitor is selected from the group consisting of AZ20, AZD0156, AZD1390, AZD6738, BAY-1895344, EPT-46464, M3541 , M4344, M6620 (formerly known as VE-922 or VX-970), NU6027, VE-821 , or an analog thereof.
• the ATR inhibitor is BAY-1895344 or an analog thereof.
• the DDRi is a WEE1 inhibitor, a Chk1 inhibitor, or a Chk2 inhibitor.
• the DDRi is a DNA-protein kinase (DNA-PK) inhibitor.
• DNA-PK DNA-protein kinase
• the mammal is a human.
• the mammal is diagnosed with cancer.
• the cancer is selected from the group comprising: breast cancer, nonsmall cell lung cancer, small cell lung cancer, pancreatic cancer, head and neck cancer, prostate cancer, colorectal cancer, sarcoma, adrenocortical carcinoma, neuroendocrine cancer, Ewing’s Sarcoma, multiple myeloma, or acute myeloid leukemia.
• the mammal has at least one solid tumor.
• said administering results in a therapeutic effect.
• said therapeutic effect comprises a decrease in tumor volume, a stable tumor volume, or a reduced rate of increase in tumor volume.
• said therapeutic effect comprises a decreased incidence of recurrence or metastasis.
• acyl represents a hydrogen or an alkyl group (e.g., a haloalkyl group), as defined herein, that is attached to the parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., a carboxyaldehyde group), acetyl, trifluoroacetyl, propionyl, butanoyl and the like.
• exemplary unsubstituted acyl groups include from 1 to 7, from 1 to 1 1 , or from 1 to 21 carbons.
• the alkyl group is further substituted with 1 , 2, 3, or 4 substituents as described herein.
• alkyl is inclusive of both straight chain and branched chain saturated groups from 1 to 20 carbons (e.g., from 1 to 10 or from 1 to 6), unless otherwise specified.
• Alkyl groups are exemplified by methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, neopentyl, and the like, and may be optionally substituted with one, two, three, or, in the case of alkyl groups of two carbons or more, four substituents independently selected from the group consisting of: (1) Ci-e alkoxy; (2) Ci-e alkylsulfinyl; (3) amino, as defined herein (e.g., unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(R n1 ) 2 , where R N1 is as defined for amino); (4) Ce-io aryl-
• R H’ is selected from the group consisting of (a1) hydrogen and (b1) C1-6 alkyl
• R 1’ is selected from the group consisting of (a2) C1-20 alkyl (e.g., C1-6 alkyl), (b2) C2-20 alkenyl (e.g., C2- 6 alkenyl), (c2) Ce-io aryl, (d2) hydrogen, (e2) C1-6 alk-Ce-io aryl, (f2) amino-Ci-20 alkyl, (g2) polyethylene glycol of -(CH 2 )s 2 (0CH 2 CH 2 )si(CH 2 )s30R’, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10
• R J’ is selected from the group consisting of (a1) hydrogen and (b1) C 1 -6 alkyl
• R K’ is selected from the group consisting of (a2) C 1-20 alkyl (e.g., C 1 -6 alkyl), (b2) C 2-20 alkenyl (e.g., C 2 - 6 alkenyl), (c2) Ce-io aryl, (d2) hydrogen, (e2) Ci-e alk-C6-io aryl, (f2) amino-Ci-20 alkyl, (g2) polyethylene glycol of -(CH 2 )s 2 (0CH 2 CH 2 )si(CH 2 )s30R’, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1
• alkylene and the prefix“alk-,” as used herein, represent a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene, and the like.
• the term“C x - y alkylene” and the prefix“C x-y alk-” represent alkylene groups having between x and y carbons.
• Exemplary values for x are 1 , 2, 3, 4, 5, and 6, and exemplary values for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-6, C1-10, C2-20, C2-6, C2-10, or C2-2o alkylene).
• the alkylene can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for an alkyl group.
• alkenyl represents monovalent straight or branched chain groups of, unless otherwise specified, from 2 to 20 carbons (e.g., from 2 to 6 or from 2 to 10 carbons) containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1 -propenyl, 2-propenyl, 2-methyl-1 - propenyl, 1 -butenyl, 2-butenyl, and the like. Alkenyls include both cis and trans isomers.
• Alkenyl groups may be optionally substituted with 1 , 2, 3, or 4 substituent groups that are selected, independently, from amino, aryl, cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, or any of the exemplary alkyl substituent groups described herein.
• alkynyl represents monovalent straight or branched chain groups from 2 to 20 carbon atoms (e.g., from 2 to 4, from 2 to 6, or from 2 to 10 carbons) containing a carbon- carbon triple bond and is exemplified by ethynyl, 1 -propynyl, and the like.
• Alkynyl groups may be optionally substituted with 1 , 2, 3, or 4 substituent groups that are selected, independently, from aryl, cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, or any of the exemplary alkyl substituent groups described herein.
• each R N1 is, independently, H, OH, NO2, N(R N2 )2, S0 2 0R N2 , S0 2 R N2 , SOR N2 , an /V-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, cycloalkyl, alkcycloalkyl, carboxyalkyl (e.g., optionally substituted with an O-protecting group, such as optionally substituted arylalkoxycarbonyl groups or any described herein), sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e.g., optionally substituted with an O- protecting group, such as optionally substituted arylalkoxycarbonyl groups or any described herein),
• Amino groups can be unsubstituted amino (i.e. , -NH2) or substituted amino (i.e., -N(R N1 )2) groups.
• amino is -NH2 or -NHR N1 , wherein R N1 is, independently, OH, NO2, NH2, NR N2 2, S0 2 0R N2 , S0 2 R N2 , SOR N2 , alkyl, carboxyalkyl, sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e.g., t-butoxycarbonylalkyl) or aryl, and each R N2 can be H, C1-20 alkyl (e.g., C1-6 alkyl), or C6-m aryl.
• amino acid refers to a molecule having a side chain, an amino group, and an acid group (e.g., a carboxy group of -C0 2 H or a sulfo group of -SOsH), wherein the amino acid is attached to the parent molecular group by the side chain, amino group, or acid group (e.g., the side chain).
• the amino acid is attached to the parent molecular group by a carbonyl group, where the side chain or amino group is attached to the carbonyl group.
• Exemplary side chains include an optionally substituted alkyl, aryl, heterocyclyl, alkaryl, alkheterocyclyl, aminoalkyl, carbamoylalkyl, and carboxyalkyl.
• Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, hydroxynorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.
• Amino acid groups may be optionally substituted with one, two, three, or, in the case of amino acid groups of two carbons or more, four substituents independently selected from the group consisting of: (1) C1-6 alkoxy; (2) C1-6 alkylsulfinyl; (3) amino, as defined herein (e.g., unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(R N1 )2, where R N1 is as defined for amino); (4) Ce-m aryl-Ci-6 alkoxy; (5) azido; (6) halo; (7) (C2-9 heterocyclyl)oxy; (8) hydroxy; (9) nitro; (10) oxo (e.g., carboxyaldehyde or acyl); (1 1) C1-7 spirocyclyl; (12) thioalkoxy; (13) thiol; (14) -CC>2R A , where R A’ is selected from the group consist
• R’ is H or Ci-20 alkyl
• R amino-polyethylene glycol of - NR N1 (CH 2 ) S 2(CH2CH 2 0) S I (CH2) S3 NR n1 , wherein s1 is an integer from 1 to 10 (e.g ., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 1 0 (e.g. , from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each R N1 is, independently, hydrogen or optionally substituted Ci-e alkyl;
• R H’ is selected from the group consisting of (a1) hydrogen and (b1) Ci-e alkyl
• R 1’ is selected from the group consisting of (a2) C1-20 alkyl (e.g., Ci-e alkyl), (b2) C2-20 alkenyl (e.g., C2- 6 alkenyl), (c2) Ce-io aryl, (d2) hydrogen, (e2) C1-6 alk-Ce-io aryl, (f2) amino-Ci-20 alkyl, (g2) polyethylene glycol of -(CH 2 )s 2 (0CH 2 CH 2 )si(CH 2 )s30R’, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to
• R’ is H or C1-20 alkyl, and (h2) amino-polyethylene glycol of -
• NR N1 (CH 2 ) S 2(CH2CH 2 0) S I (CH2) S3 NR n1 , wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each R N1 is, independently, hydrogen or optionally substituted C1-6 alkyl;
• R J’ is selected from the group consisting of (a1) hydrogen and (b1) C1-6 alkyl
• R K’ is selected from the group consisting of (a2) C1-20 alkyl (e.g., Ci-e alkyl), (b2) C2-20 alkenyl (e.g., C2- 6 alkenyl), (c2) Ce-io aryl, (d2) hydrogen, (e2) Ci-e alk-Ce-io aryl, (f2) amino-Ci-20 alkyl, (g2) polyethylene glycol of -(CH 2 )s 2 (0CH 2 CH 2 )si(CH 2 )s30R’, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to
• R’ is H or C1-20 alkyl, and (h2) amino-polyethylene glycol of -
• NR N1 (CH 2 ) S 2(CH2CH 2 0) S I (CH2) S3 NR n1 , wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each R N1 is, independently, hydrogen or optionally substituted C1-6 alkyl; and (21) amidine. In some embodiments, each of these groups can be further substituted as described herein.
• aryl represents a mono-, bicyclic, or multicyclic carbocyclic ring system having one or two aromatic rings and is exemplified by phenyl, naphthyl, 1 ,2-dihydronaphthyl,
• C1-7 acyl e.g., carboxyaldehyde
• C1-20 alkyl e.g., Ci-e alkyl, C1-6 alkoxy-Ci-6 alkyl, Ci- 6 alkylsulfinyl-Ci-6 alkyl, amino-Ci-6 alkyl, azido-Ci-6 alkyl, (carboxyaldehyde)-Ci-6 alkyl, halo-Ci-6 alkyl (e.g., perfluoroalkyl), hydroxy-Ci-6 alkyl, nitro-Ci-6 alkyl, or Ci-6 thioalkoxy-Ci-6 alkyl); (3)
• each of these groups can be further substituted as described herein.
• the alkylene group of a Ci-alkaryl or a Ci- alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and
• arylalkyl represents an aryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein.
• exemplary unsubstituted arylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C 1 -6 alk-Ce-io aryl, Ci- 10 alk-Ce-io aryl, or C1-20 alk-Ce-io aryl).
• the alkylene and the aryl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective groups.
• Other groups preceded by the prefix“alk-” are defined in the same manner, where“alk” refers to a Ci-e alkylene, unless otherwise noted, and the attached chemical structure is as defined herein.
• cyano represents an -CN group.
• cycloalkyl represents a monovalent saturated or unsaturated nonaromatic cyclic hydrocarbon group from three to eight carbons, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicycle heptyl, and the like.
• the cycloalkyl group includes one carbon-carbon double bond or one carbon-carbon triple bond
• the cycloalkyl group can be referred to as a“cycloalkenyl” or“cycloalkynyl” group respectively.
• Exemplary cycloalkenyl and cycloalkynyl groups include cyclopentenyl, cyclohexenyl, cyclohexynyl, and the like.
• Cycloalkyl groups can be optionally substituted with: (1) C1-7 acyl (e.g., carboxyaldehyde); (2) C1-20 alkyl (e.g., C1-6 alkyl, Ci-e alkoxy-Ci-6 alkyl, Ci-e alkylsulfinyl-Ci-6 alkyl, amino-Ci-6 alkyl, azido-Ci-6 alkyl, (carboxyaldehyde)-Ci-6 alkyl, halo-Ci-6 alkyl (e.g., perfluoroalkyl), hydroxy-Ci-6 alkyl, nitro-Ci-6 alkyl, or Ci-6 thioalkoxy-Ci-6 alkyl); (3) C1-20 alkoxy (e.g., Ci-
• each of these groups can be further substituted as described herein.
• the alkylene group of a Ci-alkaryl or a Ci-alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.
• diastereomer as used herein means stereoisomers that are not mirror images of one another and are non-superimposable on one another.
• enantiomer means each individual optically active form of a compound, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.
• halogen represents a halogen selected from bromine, chlorine, iodine, or fluorine.
• heteroalkyl refers to an alkyl group, as defined herein, in which one or two of the constituent carbon atoms have each been replaced by nitrogen, oxygen, or sulfur.
• the heteroalkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkyl groups.
• heteroalkenyl and heteroalkynyl refer to alkenyl and alkynyl groups, as defined herein, respectively, in which one or two of the constituent carbon atoms have each been replaced by nitrogen, oxygen, or sulfur.
• the heteroalkenyl and heteroalkynyl groups can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkyl groups.
• heteroaryl represents that subset of heterocyclyls, as defined herein, which are aromatic: i.e., they contain 4n+2 pi electrons within the mono- or multicyclic ring system.
• Exemplary unsubstituted heteroaryl groups are of 1 to 12 (e.g., 1 to 1 1 , 1 to 10, 1 to 9, 2 to 12, 2 to 1 1 , 2 to 10, or 2 to 9) carbons.
• the heteroaryl is substituted with 1 , 2, 3, or 4 substituents groups as defined for a heterocyclyl group.
• heteroarylalkyl refers to a heteroaryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein.
• exemplary unsubstituted heteroarylalkyl groups are from 2 to 32 carbons (e.g., from 2 to 22, from 2 to 18, from 2 to 17, from 2 to 16, from 3 to 15, from 2 to 14, from 2 to 13, or from 2 to 12 carbons, such as C1-6 alk-Ci-12 heteroaryl, CMO alk-Ci-12 heteroaryl, or C 1-20 alk-Ci- 12 heteroaryl).
• the alkylene and the heteroaryl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective group.
• Heteroarylalkyl groups are a subset of heterocyclylalkyl groups.
• heterocyclyl represents a 5-, 6- or 7-membered ring, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
• the 5-membered ring has zero to two double bonds, and the 6- and 7-membered rings have zero to three double bonds.
• Exemplary unsubstituted heterocyclyl groups are of 1 to 12 (e.g., 1 to 1 1 , 1 to 10, 1 to 9, 2 to 12, 2 to 1 1 , 2 to 10, or 2 to 9) carbons.
• heterocyclyl also represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons and/or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., a quinuclidinyl group.
• heterocyclyl includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one, two, or three carbocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring, such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like.
• fused heterocyclyls include tropanes and 1 ,2,3,5,8,8a-hexahydroindolizine.
• Heterocyclics include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl,
• tetrahydrothienyl dihydrothienyl, dihydroindolyl, dihydroquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, and the like, including dihydro and tetrahydro forms thereof, where one or more double bonds are reduced and replaced with hydrogens.
• Still other exemplary heterocyclyls include: 2,3,4,5-tetrahydro-2-oxo- oxazolyl; 2,3-dihydro-2-oxo-1 H-imidazolyl; 2,3,4,5-tetrahydro-5-oxo-1 H-pyrazolyl (e.g., 2,3,4,5-tetrahydro- 2-phenyl-5-oxo-1 H-pyrazolyl); 2,3,4,5-tetrahydro-2,4-dioxo-1 H-imidazolyl (e.g., 2,3,4,5-tetrahydro-2,4- dioxo-5-methyl-5-phenyl-1 H-imidazolyl); 2,3-dihydro-2-thioxo-1 ,3,4-oxadiazolyl (e.g., 2,3-dihydro-2-thioxo- 5-phenyl-1 ,3,4-oxadiazolyl); 4, 5-dihydro-5-oxo-1 /-/-tri
• Heterocyclic groups also include groups of the formula
• E' is selected from the group consisting of -N- and -CH-;
• G' is selected from the group consisting of -CH- and -N-.
• any of the heterocyclyl groups mentioned herein may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of: (1) C1-7 acyl (e.g., carboxyaldehyde ); (2) C1-20 alkyl (e.g., C1-6 alkyl, C1-6 alkoxy-Ci-6 alkyl, C1-6 alkylsulfinyl-Ci-6 alkyl, amino-Ci-6 alkyl, azido-Ci-6 alkyl, (carboxyaldehyde)-Ci-6 alkyl, halo-Ci-6 alkyl (e.g., perfluoroalkyl), hydroxy-Ci-6 alkyl, nitro-Ci-6 alkyl, or C1-6 thioalkoxy-Ci-6 alkyl); (3) C1-20 alkoxy (e.g., C1-6 alkoxy, such as perfluoroalkoxy); (4) C1-6 alkylsulfinyl;
• each of these groups can be further substituted as described herein.
• alkylene group of a Ci-alkaryl or a Ci-alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.
• hydrocarbon represents a group consisting only of carbon and hydrogen atoms.
• hydroxyl represents an -OH group.
• the hydroxyl group can be substituted with 1 , 2, 3, or 4 substituent groups (e.g., O-protecting groups) as defined herein for an alkyl.
• isomer means any tautomer, stereoisomer, enantiomer, or diastereomer of any compound. It is recognized that the compounds can have one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e. , geometric E/Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis/trans isomers).
• stereoisomers such as double-bond isomers (i.e. , geometric E/Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis/trans isomers).
• stereomers depicted herein encompass all of the corresponding stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, e.g., racemates.
• Enantiomeric and stereoisomeric mixtures of compounds can typically be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
• Enantiomers and stereoisomers can also be obtained from stereomerically or
• V-protected amino refers to an amino group, as defined herein, to which is attached one or two /V-protecting groups, as defined herein.
• /V-protecting group represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used /V-protecting groups are disclosed in Greene,“Protective Groups in Organic Synthesis,” 3 rd Edition (John Wiley &
• /V-protecting groups include acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2- bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4- chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, phenylalanine, and the like; sulfonyl-containing groups such as benzenesulfonyl, p-toluenesulfonyl, and
• benzyloxycarbonyl p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,
• Preferred /V-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).
• O-protecting group represents those groups intended to protect an oxygen containing (e.g., phenol, hydroxyl, or carbonyl) group against undesirable reactions during synthetic procedures. Commonly used O-protecting groups are disclosed in Greene,“Protective Groups in Organic Synthesis,” Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference.
• O-protecting groups include acyl, aryloyl, or carbamyl groups, such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, t- butyldimethylsilyl, tri-/so-propylsilyloxymethyl, 4,4'-dimethoxytrityl, isobutyryl, phenoxyacetyl, 4- isopropylpehenoxyacetyl, dimethylformamidino, and 4-nitrobenzoyl; alkylcarbonyl groups, such as acyl, acetyl, propionyl, pival
• alkoxyalkoxycarbonyl groups such as methoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl, 2-butoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl, 2- butenoxycarbonyl, 3-methyl-2-butenoxycarbonyl, and the like; haloalkoxycarbonyls, such as 2- chloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and the like; optionally substituted arylalkoxycarbonyl groups, such as benzyloxycarbonyl, p-methylbenzyloxycarbonyl, p- methoxybenzyloxycarbonyl, p-nitrobenzyloxy
• aryloxycarbonyl groups such as phenoxycarbonyl, p-nitrophenoxycarbonyl, o-nitrophenoxycarbonyl, 2,4-dinitrophenoxycarbonyl, p-methyl- phenoxycarbonyl, m-methylphenoxycarbonyl, o-bromophenoxycarbonyl, 3,5-dimethylphenoxycarbonyl, p- chlorophenoxycarbonyl, 2-chloro-4-nitrophenoxy-carbonyl, and the like); substituted alkyl, aryl, and alkaryl ethers (e.g., trityl; methylthiomethyl; methoxymethyl; benzyloxymethyl; siloxymethyl; 2,2,2,- trichloroethoxymethyl; tetrahydropyranyl; tetrahydrofuranyl; ethoxyethyl; 1 -[2-(trimethylsilyl)ethoxy]
• aryloxycarbonyl groups such as phenoxycarbonyl,
• diphenymethylsilyl diphenymethylsilyl
• carbonates e.g., methyl, methoxymethyl, 9-fluorenylmethyl; ethyl; 2,2,2- trichloroethyl; 2-(trimethylsilyl)ethyl; vinyl, allyl, nitrophenyl; benzyl; methoxybenzyl; 3,4-dimethoxybenzyl; and nitrobenzyl
• carbonyl-protecting groups e.g., acetal and ketal groups, such as dimethyl acetal, 1 ,3- dioxolane, and the like; acylal groups; and dithiane groups, such as 1 ,3-dithianes, 1 ,3-dithiolane, and the like
• carboxylic acid-protecting groups e.g., ester groups, such as methyl ester, benzyl ester, t-butyl ester, orthoesters, and the like
• polyethylene glycol represents an alkoxy chain comprised of one or more monomer units, each monomer unit consisting of -OChbChh-.
• Polyethyelene glycol (PEG) is also sometimes referred to as polyethylene oxide (PEO) or polyoxyethylene (POE), and these terms may be considered interchangeable for the purpose of this disclosure.
• a polyethylene glycol may have the structure, -(CH 2 )s 2 (0CH 2 CH 2 )si(CH 2 )s30-, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), and each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10).
• Polyethylene glycol may also be considered to include an amino-polyethylene glycol of -NR N1 (CH 2 ) S2 (CH 2 CH 2 0) S I (CH 2 ) S3 NR n1 -, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from O to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each R N1 is, independently, hydrogen or optionally substituted Ci-e alkyl.
• s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4)
• each of s2 and s3, independently is an integer from O to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10)
• each R N1 is, independently, hydrogen or optionally substituted Ci-e alkyl.
• stereoisomer refers to all possible different isomeric as well as conformational forms which a compound may possess (e.g., a compound of any formula described herein), in particular all possible stereochemically and conformationally isomeric forms, all diastereomers, enantiomers and/or conformers of the basic molecular structure. Some compounds may exist in different tautomeric forms, all of the latter being included within the scope of the present disclosure.
• sulfonyl represents an -S(0) 2 - group.
• thiol represents an -SH group.
• the term“administered in combination,”“combined administration,” or“coadministered” means that two or more agents are administered to a subject at the same time or within an interval such that there may be an overlap of an effect of each agent on the patient.
• two or more agents that are administered in combination need not be administered together.
• they are administered within 90 days (e.g., within 80, 70, 60, 50, 40, 30, 20, 10, 5, 4, 3, 2, or 1 day(s)), within 28 days (e.g., with 14, 7, 6, 5, 4, 3, 2, or 1 day(s), within 24 hours (e.g., 12, 6, 5, 4, 3, 2, or 1 hour(s), or within about 60, 30, 15, 10, 5, or 1 minute of one another.
• the administrations of the agents are spaced sufficiently closely together such that a combinatorial effect is achieved.
• “administering” an agent to a subject includes contacting cells of said subject with the agent.
• “antibody” refers to a polypeptide whose amino acid sequence including immunoglobulins and fragments thereof which specifically bind to a designated antigen, or fragments thereof. Antibodies may be of any type (e.g., IgA, IgD, IgE, IgG, or IgM) or subtype (e.g., lgA1 , lgA2, lgG1 , lgG2, lgG3, or lgG4).
• a characteristic sequence or portion of an antibody may include amino acid sequences found in one or more regions of an antibody (e.g., variable region, hypervariable region, constant region, heavy chain, light chain, and combinations thereof).
• a characteristic sequence or portion of an antibody may include one or more polypeptide chains and may include sequence elements found in the same polypeptide chain or in different polypeptide chains.
• antigen-binding fragment refers to a portion of an antibody that retains the binding characteristics of the parent antibody.
• bifunctional chelate or“bifunctional conjugate” as used interchangeably herein, refer to a compound that contains a chelating group or metal complex thereof, a linker group, and a therapeutic moiety, targeting moiety, or cross-linking group.
• cancer refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.
• A“solid tumor cancer” is a cancer comprising an abnormal mass of tissue, e.g., sarcomas, carcinomas, and lymphomas.
• a “hematological cancer” or“liquid cancer,” as used interchangeably herein, is a cancer present in a body fluid, e.g., lymphomas and leukemias.
• chelate refers to an organic compound or portion thereof that can be bonded to a central metal or radiometal atom at two or more points.
• conjugate refers to a molecule that contains a chelating group or metal complex thereof, a linker group, and which optionally contains a therapeutic moiety, targeting moiety, or cross-linking group.
• the term“compound,” is meant to include all stereoisomers, geometric isomers, and tautomers of the structures depicted.
• the compounds described herein can be asymmetric (e.g. , having one or more stereocenters).
• Tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton.
• Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
• Examples prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1 H- and 3H-imidazole, 1 H-, 2H- and 4H- 1 ,2,4-triazole, 1 H- and 2H- isoindole, and 1 H- and 2H-pyrazole.
• Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
• substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual subcombination of the members of such groups and ranges.
• the term“Ci-e alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
• a phrase of the form“optionally substituted X” e.g. , optionally substituted alkyl
• X optionally substituted alkyl
• cross-linking group refers to any reactive group that is able to join two or more molecules by a covalent bond.
• the cross-linking group is an amino- reactive or thiol-reactive cross-linking group.
• the amino-reactive or thiol-reactive cross-linking group comprises an activated ester such as a hydroxysuccinimide ester, 2, 3,5,6- tetrafluorophenol ester, 4-nitrophenol ester or an imidate, anhydride, thiol, disulfide, maleimide, azide, alkyne, strained alkyne, strained alkene, halogen, sulfonate, haloacetyl, amine, hydrazide, diazirine, phosphine, tetrazine, isothiocyanate.
• an activated ester such as a hydroxysuccinimide ester, 2, 3,5,6- tetrafluorophenol ester, 4-nitrophenol ester or an imidate
• anhydride, thiol, disulfide maleimide
• azide alkyne
• strained alkyne strained alkene
• halogen, sulfonate
• the cross-linking group may be glycine- glycine-glycine and/or leucine-proline-(any amino acid)-threonine-glycine, which are the recognition sequences for coupling targeting agents with the linker using a sortase-mediated coupling reaction.
• the person having ordinary skill in the art will understand that the use of cross-linking groups are not limited to the specific constructs disclosed herein, but rather may include other known cross-linking groups.
• the terms“decrease,”“decreased,”“increase,”“increased,” or“reduction,” “reduced,” have meanings relative to a reference level.
• the reference level is a level as determined by the use of said method with a control in an experimental animal model or clinical trial.
• the reference level is a level in the same subject before or at the beginning of treatment.
• the reference level is the average level in a population not being treated by said method of treatment.
• detection agent refers to a molecule or atom which is useful in diagnosing a disease by locating the cells containing the antigen.
• detection agents include, but are not limited to, radioisotopes and radionuclides, dyes (such as with the biotin-streptavidin complex), contrast agents, luminescent agents (e.g., FITC, rhodamine, lanthanide phosphors, cyanine, and near IR dyes), and magnetic agents, such as gadolinium chelates.
• DDRi DNA damage and repair inhibitor
• an“effective amount” of an agent is that amount sufficient to effect beneficial or desired results, such as clinical results, and, as such, an“effective amount” depends upon the context in which it is being applied.
• immunoconjugate refers to a conjugate that includes a targeting moiety, such as an antibody, nanobody, affibody, or a consensus sequence from Fibronectin type III domain.
• the immunoconjugate comprises an average of at least 0.10 conjugates per targeting moiety (e.g., an average of at least 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 , 2, 4, 5, or 8 conjugates per targeting moiety).
• lower effective dose when used as a term in conjunction with an agent (e.g., a therapeutic agent) refers to a dosage of the agent which is effective therapeutically in the combination therapies of the invention and which is lower than the dose which has been determined to be effective therapeutically when the agent is used as a monotherapy in reference experiments or by virtue of other therapeutic guidance.
• pharmaceutical composition represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient.
• the pharmaceutical composition is manufactured or sold with the approval of a
• compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein.
• unit dosage form e.g., a tablet, capsule, caplet, gelcap, or syrup
• topical administration e.g., as a cream, gel, lotion, or ointment
• intravenous administration e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use
• A“pharmaceutically acceptable excipient,” as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient.
• Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids,
• disintegrants dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, radioprotectants, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration.
• excipients include, but are not limited to: ascorbic acid, histidine, phosphate buffer, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine,
• BHT butylated hydroxytoluene
• salts of the compounds described here that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, or allergic response.
• Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008.
• the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.
• Compounds may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
• These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of compounds, be prepared from inorganic or organic bases.
• the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases.
• Suitable pharmaceutically acceptable acids and bases are well-known in the art, such as hydrochloric, sulphuric, hydrobromic, acetic, lactic, citric, or tartaric acids for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines for forming basic salts. Methods for preparation of the appropriate salts are well- established in the art.
• Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate,
• alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
• polypeptide refers to a string of at least two amino acids attached to one another by a peptide bond.
• a polypeptide may include at least 3-5 amino acids, each of which is attached to others by way of at least one peptide bond.
• polypeptides can include one or more“non-natural” amino acids or other entities that nonetheless are capable of integrating into a polypeptide chain.
• a polypeptide may be glycosylated, e.g., a polypeptide may contain one or more covalently linked sugar moieties.
• a single“polypeptide” e.g., an antibody polypeptide
• radioconjugate refers to any conjugate that includes a radioisotope or radionuclide, such as any of the radioisotopes or radionuclides described herein.
• radioimmunoconjugate refers to any immunoconjugate that includes a radioisotope or radionuclide, such as any of the radioisotopes or radionuclides described herein.
• radioimmunotherapy refers a method of using a
• radioimmunotherapy may include administration of a radioimmunoconjugate to a subject in need thereof, wherein administration of the radioimmunoconjugate produces a therapeutic effect in the subject.
• radioimmunotherapy may include administration of a radioimmunoconjugate to a cell, wherein administration of the radioimmunoconjugate kills the cell.
• radioimmunotherapy involves the selective killing of a cell, in some embodiments the cell is a cancer cell in a subject having cancer.
• radioactive decay refers to an atom capable of undergoing radioactive decay
• radioactive nuclide may also be used to describe a radionuclide.
• Radionuclides may be used as detection agents, as described above.
• the radionuclide is an alpha-emitting radionuclide.
• subject is meant a human or non-human animal (e.g., a mammal).
• substantially identical is meant a polypeptide sequence that has the same polypeptide sequence, respectively, as a reference sequence, or has a specified percentage of amino acid residues, respectively, that are the same at the corresponding location within a reference sequence when the two sequences are optimally aligned.
• an amino acid sequence that is “substantially identical” to a reference sequence has at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the reference amino acid sequence.
• the length of comparison sequences will generally be at least 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 50, 75, 90, 100, 150, 200, 250, 300, or 350 contiguous amino acids (e.g., a full-length sequence).
• Sequence identity may be measured using sequence analysis software, e.g., on the default setting (e.g., Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wl 53705). Such software may match similar sequences by assigning degrees of homology to various substitutions, deletions, and other modifications.
• targeting moiety refers to any molecule or any part of a molecule that binds to a given target.
• the targeting moiety is a protein or polypeptide such as an antibody or antigen binding fragment thereof, a nanobody, an affibody, or a consensus sequence from a Fibronectin type III domain.
• therapeutic moiety refers to any molecule or any part of a molecule that confers a therapeutic benefit.
• the therapeutic moiety is a protein or polypeptide, e.g., an antibody, an antigen-binding fragment thereof.
• the therapeutic moiety is a small molecule.
• beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable.
• tumor-associated antigen means an antigen that is present on tumor cells at a significantly greater amount than on normal cells.
• tumor-specific antigen refers to an antigen that is endogenously present only on tumor cells.
• Figure 1 is a schematic demonstrating the dosing schedule for [ 225 Ac]-FPI-1434 and BAY-1895344 (an ATR inhibitor) in two xenograft models: Colo-205 and A549. See Example 1 .
• Figures 2A-2B illustrate the relative tumor volume in Colo-205 (Figure 2A) and A549 ( Figure 2B) after treatment with BAY-1895344 and [ 225 Ac]-FPI-1434 alone or in combination. See Example 1 .
• Figure 3 is a schematic demonstrating the dosing schedule for [ 225 Ac]-FPI-1434 and BAY-1895344 in the Colo-205 (colorectal cancer) xenograft model. See Example 2.
• Figure 4 illustrates the relative tumor volume in Colo-205 after treatment with BAY-1895344 and [ 225 Ac]- FPI-1434 alone or in combination. See Example 2.
• Figure 5 is a schematic demonstrating the dosing schedule for olaparib for treatment in two xenograft models: Colo-205 and A549. See Example 3.
• Figures 6A-6B illustrate relative tumor volume in Colo-205 ( Figure 6A) and A549 ( Figure 6B) after treatment with olaparib. See Example 3.
• Figure 7 is a schematic demonstrating the dosing schedule for [ 225 Ac]-FPI-1434 and olaparib for treatment in two xenograft models: Colo-205 and A549. See Example 4.
• Figures 8A-8B illustrate relative tumor volume in Colo-205 ( Figure 8A) and A549 ( Figure 8B) after treatment with olaparib and [ 225 Ac]-FPI-1434 alone or in combination. See Example 4.
• Figure 9 is a schematic demonstrating the dosing schedule for [ 225 Ac]-FPI-1434 and olaparib for treatment in the Colo-205 xenograft model. See Example 5.
• Figure 10 illustrates relative tumor volume in Colo-205 after treatment with olaparib and [ 225 Ac]-FPI-1434 alone or in combination. See Example 5.
• Figure 1 1 is a schematic demonstrating the dosing schedule for [ 225 Ac]-FPI-1434 and olaparib used in the multiple-dose in vivo experiments described in Example 6.
• Figure 12 shows relative tumor volumes in animals administered lower effective doses of [ 225 Ac]-FPI-1434 (20 nCi) and olaparib (25 mg/kg) in the experiment described in Example 6.
• Figures 13A-13C show relative tumor volumes in animals administered 20 nCi (Figure 13A), 50 nCi ( Figure 13B), or 100 nCi ( Figure 13C) [ 225 Ac]-FPI-1434 with olaparib (25 mg/kg or 50 mg/kg).
• the present disclosure relates to combination therapies for treating or ameliorating cancer, using radioimmunoconjugates and DNA damage and repair inhibitors (DDRis).
• DDRis DNA damage and repair inhibitors
• a lower effective dose of the radioimmunoconjugate and/or of the DDRi is used.
• Radiolabelled targeting moieties are designed to target a protein or receptor that is upregulated in a disease state and/or specific to diseased cells (e.g., tumor cells) to deliver a radioactive payload to damage and kill cells of interest.“Radioimmunotherapy” refers to this therapy when the targeting moiety comprises an antibody, typically a monoclonal antibody.
• Radioactive decay of the payload produces an alpha, beta, or gamma particle or Auger electron that can cause direct effects to DNA (such as single or double stranded DNA breaks) or indirect effects such as by-stander or crossfire effects.
• Radioimmunoconjugates typically contain a biological targeting moiety (e.g., an antibody or antigen binding fragment thereof that specifically binds to a molecule expressed on or by a tumor, e.g., IGF-1 R or TEM-1/endosialin), a chelating moiety or a metal complex of a chelating moiety (e.g., comprising a radioisotope), and a linker.
• Conjugates may be formed by appending a bifunctional chelate to the biological targeting molecule so that structural alterations are minimal while maintaining target affinity.
• a radioimmunoconjugate may be formed by radiolabelling such a conjugate.
• Bifunctional chelates structurally contain a chelate, a linker, and a cross-linking group. When developing new bifunctional chelates, most efforts focus around the chelating portion of the molecule. Several examples of bifunctional chelates have been described with various cyclic and acyclic structures conjugated to a targeted moiety. [Bioconjugate Chem. 2000, 11 , 510-519, Bioconjugate Chem.2012, 23, 1029-1039, Mol Imaging Biol (2011) 13:215-221 , Bioconjugate Chem.2002,13,1 10-115]
• Radioimmunoconjugates suitable for use in accordance with the present disclosure generally have the structure of Formula l-a:
• B is a targeting moiety
• L is a linker
• the radioimmunoconjugate comprises the following structure:
• B is the targeting moiety
• Targeting moieties include any molecule or any part of a molecule that is capable of binding to a given target.
• the targeting moiety comprises a protein or polypeptide.
• the targeting moiety is selected from the group consisting of antibodies or antigen binding fragments thereof, nanobodies, affibodies, and consensus sequences from Fibronectin type III domains (e.g., Centyrins or Adnectins).
• a moiety is both a targeting and a therapeutic moiety, i.e. , the moiety is capable of binding to a given target and also confers a therapeutic benefit.
• Antibodies typically comprise two identical light polypeptide chains and two identical heavy polypeptide chains linked together by disulfide bonds.
• the first domain located at the amino terminus of each chain is variable in amino acid sequence, providing the antibody-binding specificities of each individual antibody. These are known as variable heavy (VH) and variable light (VL) regions.
• the other domains of each chain are relatively invariant in amino acid sequence and are known as constant heavy (CH) and constant light (CL) regions.
• Light chains typically comprise one variable region (VL) and one constant region (CL).
• An IgG heavy chain includes a variable region (VH), a first constant region (CH1), a hinge region, a second constant region (CH2), and a third constant region (CH3).
• the heavy chain includes an additional constant region (CH4).
• Antibodies described herein can include, for example, monoclonal antibodies, polyclonal antibodies, multispecific antibodies, human antibodies, humanized antibodies, camelid antibodies, chimeric antibodies, single-chain Fvs (scFv), disulfide-linked Fvs (sdFv), and anti-idiotypic (anti-id) antibodies, and antigen-binding fragments of any of the above.
• the antibody or antigen-binding fragment thereof is humanized.
• the antibody or antigen-binding fragment thereof is chimeric.
• Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., lgG1 , lgG2, lgG3, lgG4, lgA1 and lgA2) or subclass.
• type e.g., IgG, IgE, IgM, IgD, IgA and IgY
• class e.g., lgG1 , lgG2, lgG3, lgG4, lgA1 and lgA2 or subclass.
• an“antigen binding fragment” of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen.
• binding fragments encompassed within the term“antigen binding fragment” of an antibody include a Fab fragment, a F(ab')2 fragment, a Fd fragment, a Fv fragment, a scFv fragment, a dAb fragment (Ward et al., (1989) Nature 341 :544-546), and an isolated complementarity determining region (CDR).
• an“antigen binding fragment” comprises a heavy chain variable region and a light chain variable region.
• Antibodies or fragments described herein can be produced by any method known in the art for the synthesis of antibodies (see, e.g., Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Brinkman et al., 1995, J. Immunol. Methods 182:41-50; WO 92/22324; WO 98/46645).
• Chimeric antibodies can be produced using the methods described in, e.g., Morrison, 1985, Science 229:1202, and humanized antibodies by methods described in, e.g., U.S. Pat. No. 6,180,370.
• Additional antibodies described herein are bispecific antibodies and multivalent antibodies, as described in, e.g., Segal et al., J. Immunol. Methods 248:1-6 (2001); and Tutt et al., J. Immunol. 147: 60 (1991).
• IGF-1R Insulin-like growth factor 1
• Insulin-like growth factor 1 receptor is a transmembrane protein found on the surface of human cells activated by insulin-like growth factor 1 (IGF-1) and 2 (IGF-2).
• IGF-1 insulin-like growth factor 1
• IGF-2 insulin-like growth factor 2
• radioimmunoconjugates comprise antibodies against insulin-like growth factor-1 receptor (IGF-1 R).
• IGF-1 R insulin-like growth factor-1 receptor
• IGF-1 R promotes initiation and progression of cancer, playing a critical role in mitogenic transformation and maintenance of the transformed phenotype.
• IGF-1 R has been associated with development of multiple common cancers including breast, lung (e.g., non-small lung), liver, prostate, pancreas, ovarian, colon, melanoma, adrenocortical carcinoma, and various types of sarcomas.
• IGF-1 R signaling stimulates tumour cell proliferation and metabolism, supports angiogenesis, and confers protection from apoptosis. It affects metastatic factors (e.g., HIF-1 dependent hypoxia signaling), anchorage independent growth, as well as growth and survival of tumour metastases after extravasation.
• IGF-1 R has also been implicated in the development, maintenance and enrichment of therapeutic resistant cancer stem cell populations.
• Radioimmunotherapy may provide a viable mechanism for treating cancers overexpressing the IGF-1 receptor by utilizing the ability of IGF-1 R to undergo antibody triggered internalization and lysosomal degradation to deliver targeted radioisotopes inside cancer cells.
• IGF-1 R targeted radioimmunoconjugate prolongs the residence time of the delivered radioisotope inside cancer cells, thereby maximizing the potential for a cell killing emission to occur.
• actinium-225 which yields 4 alpha particles per decay chain
• cell death can be accomplished by as little as 1 atom of radionuclide delivered per cell [Sgouros, et al. J Nucl Med. 2010, 51 :311-2]
• Cell killing due to direct DNA impact and breakage by an alpha particle may occur in the targeted cell or in a radius of 2 or 3 non-targeted cells for a given alpha particle decay.
• IGF-1 R targeted radioimmunoconjugates may not generate mechanistic resistance as they do not rely on blocking ligand binding to the receptor to inhibit the oncologic process, as needed with a therapeutic antibody.
• IGF-1 R antibodies have been developed and investigated for the treatment of various types of cancers, including figitumumab, cixutumumab, ganitumab, AVE1642 (also known as humanized EM164 and huEM164), BIIB002, robatumumab, and teprotumumab. After binding to IGF-1 R, these antibodies are internalized into the cell and degraded by lysosomal enzymes. The combination of overexpression on tumor cells and internalization offers the possibility of delivering detection agents directly to the tumor site while limiting the exposure of normal tissues to toxic agents.
• the CDRs of the light chain variable region of AVE1642 have the sequences:
• the light chain variable region of AVE1642 has the sequence:
• the CDRs of the heavy chain variable region of AVE1642 have the sequences:
• Endosialin also known as TEM-1 or CD-248, is an antigen expressed by tumor-associated endothelial cells, stromal cells, and pericytes.
• endosialin antibodies examples include hMP-E-8.3 (disclosed in WO 2017/134234, the entire contents of which are incorporated by reference herein) and ontuxizumab (MORAb-004).
• the endosialin antibody or antigen-binding fragment thereof recognizes an epitope having an amino acid sequence of SRDHQIPVIAAN (SEQ ID NO: 9).
• the heavy chain variable region of the endosialin antibody or antibodybinding fragment thereof comprises the complementarity determining regions (CDRs) having the following sequences:
• CDR-H1 GYGVN (SEQ ID NO: 10) or GFSLTGYGVN (SEQ ID NO: 1 1)
• the light chain variable region of the endosialin antibody or antibodybinding fragment thereof comprises the complementarity determining regions (CDRs) having the following sequences:
• CDR-L2 KASNLHT (SEQ ID NO: 15)
• the endosialin antibody or antigen-binding fragment thereof is a humanized antibody.
• the heavy chain variable region of the endosialin antibody or antigenbinding fragment thereof comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 17, 18, 19, or 20:
• the light chain variable region of the endosialin antibody or antigenbinding fragment thereof comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 21 , 22, 23, or 24:
• Humanized VL4 DIQMTQSPSSLSASVGDRVTITCHASQNINVWLTWYQQKPEKAPKSLIYKASNLHTGVPS
• Nanobodies are antibody fragments consisting of a single monomeric variable antibody domain. Nanobodies may also be referred to as single-domain antibodies. Like antibodies, nanobodies bind selectively to a specific antigen. Nanobodies may be heavy-chain variable domains or light chain domains. Nanobodies may occur naturally or be the product of biological engineering. Nanobodies may be biologically engineered by site-directed mutagenesis or mutagenic screening (e.g., phage display, yeast display, bacterial display, mRNA display, ribosome display).
• site-directed mutagenesis or mutagenic screening e.g., phage display, yeast display, bacterial display, mRNA display, ribosome display.
• Affibodies are polypeptides or proteins engineered to bind to a specific antigen. As such, affibodies may be considered to mimic certain functions of antibodies.
• Affibodies may be engineered variants of the B-domain in the immunoglobulin-binding region of staphylococcal protein A.
• Affibodies may be engineered variants of the Z-domain, a B-domain that has lower affinity for the Fab region.
• Affibodies may be biologically engineered by site-directed mutagenesis or mutagenic screening (e.g., phage display, yeast display, bacterial display, mRNA display, ribosome display).
• Affibody molecules showing specific binding to a variety of different proteins e.g. insulin, fibrinogen, transferrin, tumor necrosis factor-a, IL-8, gp120, CD28, human serum albumin, IgA, IgE, IgM, HER2 and EGFR
• proteins e.g. insulin, fibrinogen, transferrin, tumor necrosis factor-a, IL-8, gp120, CD28, human serum albumin, IgA, IgE, IgM, HER2 and EGFR
• the Fibronectin type III domain is an evolutionarily conserved protein domain found in a wide- variety of extracellular proteins.
• the Fibronectin type III domain has been used as a molecular scaffold to produce molecules capable of selectively binding a specific antigen.
• Variants of the Fibronectin type III domains (FN3) that have been engineered for selective-binding may also be referred to as monobodies.
• FN3 domains may be biologically engineered by site-directed mutagenesis or mutagenic screening (e.g., CIS-display, phage display, yeast display, bacterial display, mRNA display, ribosome display).
• Polypeptides used in accordance with the disclosure may have a modified amino acid sequence.
• Modified polypeptides may be substantially identical to the corresponding reference polypeptide (e.g., the amino acid sequence of the modified polypeptide may have at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the amino acid sequence of the reference polypeptide).
• the modification does not destroy significantly a desired biological activity (e.g., binding to IGF-1 R or to endosialin).
• the modification may reduce (e.g., by at least 5%, 10%, 20%, 25%, 35%, 50%, 60%, 70%, 75%, 80%, 90%, or 95%), may have no effect, or may increase (e.g., by at least 5%, 10%, 25%, 50%, 100%, 200%, 500%, or 1000%) the biological activity of the original polypeptide.
• the modified polypeptide may have or may optimize a characteristic of a polypeptide, such as in vivo stability, bioavailability, toxicity, immunological activity, immunological identity, and conjugation properties.
• Modifications include those by natural processes, such as post-translational processing, or by chemical modification techniques known in the art. Modifications may occur anywhere in a polypeptide including the polypeptide backbone, the amino acid side chains and the amino- or carboxy-terminus. The same type of modification may be present in the same or varying degrees at several sites in a given polypeptide, and a polypeptide may contain more than one type of modification. Polypeptides may be branched as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic polypeptides may result from post-translational natural processes or may be made synthetically.
• modifications include pegylation, acetylation, acylation, addition of acetomidomethyl (Acm) group, ADP-ribosylation, alkylation, amidation, biotinylation, carbamoylation, carboxyethylation, esterification, covalent attachment to flavin, covalent attachment to a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of drug, covalent attachment of a marker (e.g., fluorescent or radioactive), covalent attachment of a lipid or lipid derivative, covalent attachment of phosphatidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent crosslinks, formation of cystine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic
• a modified polypeptide can also include an amino acid insertion, deletion, or substitution, either conservative or non-conservative (e.g., D-amino acids, desamino acids) in the polypeptide sequence (e.g., where such changes do not substantially alter the biological activity of the polypeptide).
• conservative or non-conservative e.g., D-amino acids, desamino acids
• the addition of one or more cysteine residues to the amino or carboxy-terminus of a polypeptide can facilitate conjugation of these polypeptides by, e.g., disulfide bonding.
• a polypeptide can be modified to include a single cysteine residue at the amino-terminus or a single cysteine residue at the carboxy-terminus.
• Amino acid substitutions can be conservative (i.e., wherein a residue is replaced by another of the same general type or group) or non-conservative (i.e., wherein a residue is replaced by an amino acid of another type).
• a naturally occurring amino acid can be substituted for a non-naturally occurring amino acid (i.e., non-naturally occurring conservative amino acid substitution or a non-naturally occurring non-conservative amino acid substitution).
• Polypeptides made synthetically can include substitutions of amino acids not naturally encoded by DNA (e.g., non-naturally occurring or unnatural amino acid).
• non-naturally occurring amino acids include D-amino acids, N-protected amino acids, an amino acid having an
• Phenylglycine may substitute for Trp, Tyr, or Phe; citrulline and methionine sulfoxide are neutral nonpolar, cysteic acid is acidic, and ornithine is basic.
• Proline may be substituted with hydroxyproline and retain the conformation conferring properties.
• Analogs may be generated by substitutional mutagenesis and retain the biological activity of the original polypeptide. Examples of substitutions identified as“conservative substitutions” are shown in Table 1 . If such substitutions result in a change not desired, then other type of substitutions, denominated“exemplary substitutions” in Table 1 , or as further described herein in reference to amino acid classes, are introduced and the products screened.
• Substantial modifications in function or immunological identity are accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain.
• chelating moieties include, but are not limited to, DOTA (1 ,4,7,10- tetraazacyclododecane-1 ,4,7,10-tetraacetic acid), DOTMA (1 R,4R,7R,10R)-a, a’, a”, a’”-tetramethyl-
• DTPA diethylenetriaminepentaacetic acid
• DTPA-BMA diethylenetriaminepentaacetic acid-bismethylamide
• HOPO octadentate hydroxypyridinones
• radioimmunoconjugates comprise a metal complex of a chelating moiety.
• chelating groups may be used in metal chelate combinations with metals, such as manganese, iron, and gadolinium and isotopes (e.g., isotopes in the general energy range of 60 to 4,000 keV), such as any of the radioisotopes and radionuclides discussed herein. 2 , 2 2 ,
• chelating moieties are useful as detection agents, and
• radioimmunoconjugates comprising such detectable chelating moieties can therefore be used as diagnostic or theranostic agents.
• the metal complex comprises a radionuclide.
• suitable radioisotopes and radionuclides include, but are not limited to, 3 H, 14 C, 15 N, 18 F, 35 S, 47 Sc, 55 Co, 60 Cu,
• the radionuclide is an alpha emitter, e.g. , Astatine-21 1 ( 211 At), Bismuth- 212 ( 212 Bi), Bismuth-213 ( 213 Bi), Actinium-225 ( 225 Ac), Radium-223 ( 223 Ra), Lead-212 ( 212 Pb), Thorium- 227 ( 227 Th), or Terbium-149 ( 149 Tb).
• Astatine-21 1 211 At
• Bismuth- 212 212 Bi
• Bismuth-213 213 Bi
• Actinium-225 225 Ac
• Radium-223 223 Ra
• Thorium- 227 227 Th
• Terbium-149 149 Tb
• the linker is as shown within the structure of Formula l-b, as that part of Formula l-b absent A and B:
• the linker is -L 1 -(L 2 ) n -,
• L 1 is optionally substituted C1-C6 alkyl, substituted C1-C6 heteroalkyl, substituted aryl or heteroaryl;
• n 1 -5;
• each L 2 independently, has the structure:
• L 3 is optionally substituted C1-C50 alkyl or optionally substituted C1-C50 heteroalkyl or C5-C20 polyethylene glycol;
• radioimmunoconjugates comprise a cross-linking group instead of or in addition to the targeting moiety or therapeutic moiety (e.g., B in Formula I comprises a cross-linking group).
• a cross-linking group is a reactive group that is able to join two or more molecules by a covalent bond.
• Cross-linking groups may be used to attach the linker and chelating moiety to a therapeutic or targeting moiety.
• Cross-linking groups may also be used to attach the linker and chelating moiety to a target in vivo.
• the cross-linking group is an amino-reactive, methionine reactive or thiol-reactive cross-linking group, or a sortase-mediated coupling.
• the amino- reactive or thiol-reactive cross-linking group comprises an activated ester such as a hydroxysuccinimide ester, 2,3,5,6-tetrafluorophenol ester, 4-nitrophenol ester or an imidate, anhydride, thiol, disulfide, maleimide, azide, alkyne, strained alkyne, strained alkene, halogen, sulfonate, haloacetyl, amine, hydrazide, diazirine, phosphine, tetrazine, isothiocyanate, or oxaziridine.
• an activated ester such as a hydroxysuccinimide ester, 2,3,5,6-tetrafluorophenol ester, 4-nitrophenol ester or an imidate
• anhydride, thiol, disulfide maleimide
• azide alkyne
• strained alkyne strained alkene
• the sortase recognition sequence may comprise of a terminal glycine-glycine-glycine (GGG) and/or LPTXG amino acid sequence, where X is any amino acid.
• GGG terminal glycine-glycine-glycine
• LPTXG amino acid sequence where X is any amino acid.
• a DNA Damage and Repair inhibitor is co-administered with a radioimmunoconjugate.
• DNA repair involves multiple molecular pathways that repair DNA single strand breaks (e.g., the PARP pathway) and double stranded breaks (e.g., BRCA and other genes such as ATR/ATM).
• PARP inhibition results in a failure of single stranded break repair, which further leads to double stranded breaks.
• Available PARP inhibitors act through both PARP enzyme inhibition and DNA-trapping. Tumor cells with BRCA and/or PTEN mutations are sensitive to PARPi.
• ATR inhibition results in a failure to repair double stranded breaks— the accumulation of double stranded breaks results in cell death. These inhibitors act by preventing homologous recombination and non-homologous end joining mechanisms.
• the DDRi is a PARP inhibitor (PARPi).
• PARPi PARP inhibitor
• the PARPi is selected from the group comprising: niparib, niraparib, olaparib, pamiparib, rucaparib (camsylate), talazoparib, veliparib, or an analog thereof.
• the DDRi is an ATM/ATR inhibitor.
• the ATM/ATR inhibitor is selected from the group comprising AZ20, AZD0156, AZD1390, AZD6738, BAY-1895344, EPT-46464, M3541 , M4344, M6620 (formerly known as VE-922 or VX-970), NU6027, VE-821 , or an analog thereof.
• the PARPi is adavosertib, AZD2811 , or an analog thereof.
• the DDRi is a WEE1 inhibitor, a Chk1 inhibitor, or a Chk2 inhibitor.
• the DDRi is a DNA-dependent protein kinase (DNA-PK) inhibitor.
• Non-limiting examples of DNA-PK inhibitors include AZD7648, KU-0060648, NU7026, NU7441 (KU-57788), PI-103, PIK-75 HCI, PP121 , SF2523, and analogs thereof.
• a therapy (e.g., comprising a therapeutic agent) is administered to a subject.
• the subject is a mammal, e.g., a human.
• the subject has received or is receiving another therapy.
• the subject has received or is receiving a radioimmunoconjugate.
• the subject has received or is receiving a DNA damage and repair inhibitor (DDRi).
• DDRi DNA damage and repair inhibitor
• the subject has cancer or is at risk of developing cancer.
• the subject may have been diagnosed with cancer.
• the cancer may be a primary cancer or a metastatic cancer.
• Subjects may have any stage of cancer, e.g., stage I, stage II, stage III, or stage IV with or without lymph node involvement and with or without metastases.
• Provided compositions may prevent or reduce further growth of the cancer and/or otherwise ameliorate the cancer (e.g., prevent or reduce metastases).
• the subject does not have cancer but has been determined to be at risk of developing cancer, e.g., because of the presence of one or more risk factors such as environmental exposure, presence of one or more genetic mutations or variants, family history, etc.
• the subject has not been diagnosed with cancer.
• the cancer is a solid tumor.
• the solid tumor cancer is breast cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, head and neck cancer, prostate cancer, colorectal cancer, sarcoma, adrenocortical carcinoma, neuroendocrine cancer, Ewing's Sarcoma, multiple myeloma, or acute myeloid leukemia.
• the cancer is a non-solid (e.g., liquid (e.g., hematologic)) cancer.
• the present disclosure provides combination therapies in which the amounts of each therapeutic may or may not be, on their own, therapeutically effective.
• methods comprising administering a first therapy and a second therapy in amounts that together are effective to treat or ameliorate a disorder, e.g., cancer.
• a disorder e.g., cancer.
• at least one of the first and second therapy is administered to the subject in a lower effective dose.
• both the first and the second therapies are administered in lower effective doses.
• the first therapy comprises a radioimmunoconjugate and the second therapy comprises a DNA damage response inhibitor (DDRi).
• DDRi DNA damage response inhibitor
• the first therapy comprises a DDRi and the second therapy comprises a radioimmunoconjugate.
• therapeutic combinations as disclosed herein are administered to a subject in a manner (e.g., dosing amount and timing) sufficient to cure or at least partially arrest the symptoms of the disorder and its complications.
• a“monotherapy” an amount adequate to accomplish this purpose is defined as a“therapeutically effective amount,” an amount of a compound sufficient to substantially improve at least one symptom associated with the disease or a medical condition.
• The“therapeutically effective amount” typically varies depending on the therapeutic. For known therapeutic agents, the relevant therapeutically effective amounts may be known to or readily determined by those of skill in the art.
• an agent or compound that decreases, prevents, delays, suppresses, or arrests any symptom of the disease or condition would be therapeutically effective.
• a therapeutically effective amount of an agent or compound is not required to cure a disease or condition but will provide a treatment for a disease or condition such that the onset of the disease or condition is delayed, hindered, or prevented, or the disease or condition symptoms are ameliorated, or the term of the disease or condition is changed or, for example, is less severe or recovery is accelerated in an individual.
• a treatment may be therapeutically effective if it causes a cancer to regress or to slow the cancer’s growth.
• the dosage regimen (e.g., amounts of each therapeutic, relative timing of therapies, etc.) that is effective for these uses may depend on the severity of the disease or condition and the weight and general state of the subject.
• the therapeutically effective amount of a particular composition comprising a therapeutic agent applied to mammals can be determined by the ordinarily- skilled artisan with consideration of individual differences in age, weight, and the condition of the mammal.
• the dosage of these compounds can be lower than (e.g., less than or equal to about 90%, 75%, 50%, 40%, 30%, 20%, 15%, 12%, 10%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, 0.5%, or 0.1 % of) the equivalent dose of required for a therapeutic effect of the unconjugated agent.
• Therapeutically effective and/or optimal amounts can also be determined empirically by those of skill in the art. Thus, lower effective doses can also be determined by those of skill in the art.
• Single or multiple administrations of a composition can be carried out with dose levels and pattern being selected by the treating physician.
• the dose and administration schedule can be determined and adjusted based on the severity of the disease or condition in the subject, which may be monitored throughout the course of treatment according to the methods commonly practiced by clinicians or those described herein.
• the first and second therapies may be any combination therapy methods.
• the first and second therapies may be any combination therapy methods.
• a first composition comprising a first therapeutic agent and a second composition comprising a second therapeutic agent may be administered sequentially or concurrently to a subject.
• a composition comprising a combination of a first therapeutic agent and a second therapeutic agent may be administered to the subject.
• the radioimmunoconjugate is administered in a single dose. In some embodiments, the radioimmunoconjugate is administered more than once.
• radioimmunoconjugate is administered more than once, the dose of each administration may be the same or different.
• the DDRi is administered in a single dose. In some embodiments, the DDRi is administered more than once, e.g., at least twice, at least three times, etc. In some embodiments, the DDRi is administered multiple times according to a regular or semi-regular schedule, e.g., once every approximately two weeks, once a week, twice a week, three times a week, or more than three times a week.
• the dose of each administration may be the same or different. For example, the DDRi may be administered in an initial dose amount, and then subsequent dosages of the DDRi may be higher or lower than the initial dose amount.
• the first dose of the DDRi is administered at the same time as the first dose of the radioimmunoconjugate. In some embodiments, the first dose of the DDRi is administered before the first dose of radioimmunoconjugate. In some embodiments, the first dose of the DDRi is administered after the first dose of radioimmunoconjugate. In some embodiments, subsequent doses of the DDRi are administered.
• radioimmunoconjugates (or a composition thereof) and DDRis (or a composition thereof) are administered within 28 days (e.g., within 14, 7, 6, 5, 4, 3, 2, or 1 day(s)) of each other.
• radioimmunoconjugates (or a composition thereof) and DDRis (or a composition thereof) are administered within 90 days (e.g., within 80, 70, 60, 50, 40, 30, 20, 10, 5, 4, 3, 2, or 1 day(s)) of each other.
• the DDRi is administered at the same time as radioimmunoconjugate.
• the DDRi is administered multiple times after the first administration of radioimmunoconjugate.
• compositions are administered for radiation treatment planning or diagnostic purposes.
• compositions may be administered to a subject in a diagnostically effective dose and/or an amount effective to determine the therapeutically effective dose.
• a first dose of disclosed conjugate or a composition (e.g., pharmaceutical composition) thereof is administered in an amount effective for radiation treatment planning, followed administration of a combination therapy including a conjugate as disclosed herein and another therapeutic.
• compositions comprising one or more agents (e.g., radioimmunoconjugates and/ or DDRis) can be formulated for use in accordance with disclosed methods and systems in a variety of drug delivery systems.
• agents e.g., radioimmunoconjugates and/ or DDRis
• One or more physiologically acceptable excipients or carriers can also be included in the composition for proper formulation. Examples of suitable formulations are found in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 17th ed., 1985.
• suitable formulations are found in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 17th ed., 1985.
• Langer Science 249:1527-1533, 1990.
• compositions may be formulated for parenteral, intranasal, topical, oral, or local administration, such as by a transdermal means, for prophylactic and/or therapeutic treatment.
• compositions can be administered parenterally (e.g., by intravenous, intramuscular, or subcutaneous injection), or by oral ingestion, or by topical application or intraarticular injection at areas affected by the vascular or cancer condition.
• parenterally e.g., by intravenous, intramuscular, or subcutaneous injection
• oral ingestion or by topical application or intraarticular injection at areas affected by the vascular or cancer condition.
• additional routes of administration include intravascular, intra-arterial, intratumor, intraperitoneal, intraventricular, intraepidural, as well as nasal, ophthalmic, intrascleral, intraorbital, rectal, topical, or aerosol inhalation administration.
• sustained release administration by such means as depot injections or erodible implants or components.
• compositions comprising include agents (e.g., compounds as disclosed herein) dissolved or suspended in an acceptable carrier, preferably an aqueous carrier, e.g., water, buffered water, saline, or PBS, among others, e.g., for parenteral administration.
• an acceptable carrier preferably an aqueous carrier, e.g., water, buffered water, saline, or PBS, among others, e.g., for parenteral administration.
• Compositions may contain pharmaceutically acceptable auxiliary substances to approximate
• compositions are formulated for oral delivery; for example, compositions may contain inert ingredients such as binders or fillers for the formulation of a unit dosage form, such as a tablet or a capsule.
• compositions are formulated for local administration; for example, compositions may contain inert ingredients such as solvents or emulsifiers for the formulation of a cream, an ointment, a gel, a paste, or an eye drop.
• Compositions may be sterilized, e.g., by conventional sterilization techniques, or sterile filtered.
• Aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
• the pH of the preparations typically will be between 3 and 11 , more preferably between 5 and 9 or between 6 and 8, and most preferably between 6 and 7, such as 6 to 6.5.
• compositions in solid form are packaged in multiple single dose units, each containing a fixed amount of the above-mentioned agent or agents, such as in a sealed package of tablets or capsules.
• compositions in solid form are packaged in a container for a flexible quantity, such as in a squeezable tube designed for a topically applicable cream or ointment.
• disclosed methods further include administering an antiproliferative agent, radiation sensitizer, or an immunoregulatory or immunomodulatory agent.
• antiproliferative or“antiproliferative agent,” as used interchangeably herein, is meant any anticancer agent, including those antiproliferative agents listed in Table 2, any of which can be used in combination with a radioimmunoconjugate to treat a condition or disorder.
• Antiproliferative agents also include organo-platinum derivatives, naphtoquinone and benzoquinone derivatives, chrysophanic acid and anthroquinone derivatives thereof.
• immuno-modulator or“immunomodulatory agent,” as used interchangeably herein, is meant any immuno-modulator, including those listed in Table 2, any of which can be used in combination with a radioimmunoconjugate.
• Radiation sensitizer includes any agent that increases the sensitivity of cancer cells to radiation therapy.
• Radiation sensitizers may include, but are not limited to, 5-fluorouracil, analogs of platinum (e.g., cisplatin, carboplatin, oxaliplatin), gemcitabine, EGFR antagonists (e.g., cetuximab, gefitinib), farnesyltransferase inhibitors, COX-2 inhibitors, bFGF antagonists, and VEGF antagonists.
• FPI-1434 was given as a single agent at doses sub-optimal for tumor regression (50 nCi) in a Colo-205 (colorectal cancer) xenograft model.
• the first dose of BAY-1895344 was administered 24 hours following FPI-1434 administration. See Figure 3.
• NSCLC NSCLC xenograft model.
• Olaparib showed modest efficacy as a single agent in both models ( Figure 6A and 6B). There did not appear to be a dose response for either model, and immunohistochemical analysis of y-H2AX foci showed no increase in DSB formation after olaparib treatment.
• FPI-1434 was given as a single agent at doses sub-optimal for tumor regression (50 nCi) in a Colo-205 (colorectal cancer) xenograft model.
• the first dose of olaparib was administered 24 hours following FPI-1434 administration. See Figure 9.
• FIG. 12 shows results using lower effective doses of [ 225 Ac]-FPI-1434 (20 nCi) and olaparib (25 mg/kg). Whereas no or limited therapeutic effect was observed with either [ 225 Ac]-FPI-1434 or olaparib alone, animals that received the combination therapy demonstrated significantly lower tumor volumes when compared with animals that received either treatment alone.
• Figure 13A-13C show results using 20 nCi ( Figure 13A), 50 nCi ( Figure 13B), or 100 nCi ( Figure 13C) [ 225 Ac]-FPI-1434 with olaparib (25 mg/kg or 50 mg/kg). The strongest combination effects were observed at the lowest single agent doses. See Figure 13A.

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