WO2022029223A1 - Combination therapy comprising anti-kaag1 antibody drug conjugate and parp inhibitor - Google Patents
Combination therapy comprising anti-kaag1 antibody drug conjugate and parp inhibitor Download PDFInfo
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- WO2022029223A1 WO2022029223A1 PCT/EP2021/071861 EP2021071861W WO2022029223A1 WO 2022029223 A1 WO2022029223 A1 WO 2022029223A1 EP 2021071861 W EP2021071861 W EP 2021071861W WO 2022029223 A1 WO2022029223 A1 WO 2022029223A1
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Classifications
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/68035—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a pyrrolobenzodiazepine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6843—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a material from animals or humans
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present disclosure relates to combination therapies for the treatment of pathological conditions, such as cancer.
- the present disclosure relates to combination therapies comprising treatment with an anti-KAAG1 Antibody Drug Conjugate (anti-KAAG1 ADC) and a PARP inhibitor.
- anti-KAAG1 ADC anti-KAAG1 Antibody Drug Conjugate
- PARP inhibitor a PARP inhibitor
- ADC antibody-drug conjugates
- cytotoxic or cytostatic agents i.e. drugs to kill or inhibit tumour cells in the treatment of cancer
- cytotoxic or cytostatic agents i.e. drugs to kill or inhibit tumour cells in the treatment of cancer
- systemic administration of these unconjugated drug agents may result in unacceptable levels of toxicity to normal cells
- the KAAG1 peptide is encoded by the antisense strand of the RU2 gene (Van den Eynde et al., J Exp Med (1999) 190 (12): 1793-1800).
- This antisense transcript - ru2AS - is expressed as an 84 amino acid peptide in a high proportion of tumors of various histological types, including melanomas, sarcomas and colorectal carcinomas. It is absent in most normal tissues, but is expressed at lower levels in testis, kidney, urinary bladder, and liver. Quantification has indicated that expression levels in healthy tissue are in the region of 16-31 % (testis), 7-19% (kidney), or 6% (Bladder & liver) of those found in the LE9211-RCC carcinoma cell line.
- the expression product of the sense strand of the RU2 gene - ru2S - encodes a longer protein with potentially functional domains that is expressed at higher levels and in most tested tissues. This suggests a housekeeping function for RU2S, which is consistent with the presence of a CpG island in its promoter and in most of exon 1 . Therefore, the KAAG1 antigen is not tumor specific, but corresponds to a self-antigen with restricted tissue distribution and expression in healthy tissue.
- an Antibody Drug Conjugate comprising an anti-KAAG1 antibody (an anti KAAG1-ADC) in the treatment of, for example, cancer has been established - see, for example, PCT/EP2020/065506.
- the present authors have determined that the administration of a combination of an anti-KAAG1 ADC and PARP inhibitor to an individual leads to unexpected clinical advantages.
- the present authors have further determined that administration of an anti- KAAG1 ADC to an individual that has either been treated with, or is being treated with, and PARP inhibitor leads to a synergistic increase in treatment efficacy.
- the present disclosure provides a method of selecting an individual as suitable for treatment with an anti-KAAG1 ADC, wherein the individual is selected for treatment with the anti-KAAG1 ADC if the individual has been treated, or is being treated, with a PARP inhibitor.
- the individual may be selected for treatment if the individual is refractory to treatment, or further treatment, with the PARP inhibitor.
- the present disclosure provides a method for treating a disorder in an individual, the method comprising selecting an individual as suitable for treatment by a method of the first aspect, and then administering to the individual an effective amount of the anti-KAAG1 ADC.
- the method of treatment may further comprise administering a PARP inhibitor in combination with the anti-KAAG1 ADC.
- the disclosure provides a method for treating a disorder in an individual, the method comprising administering to the individual an effective amount of an anti-KAAG1 ADC and PARP inhibitor.
- the individual may be selected for treatment according to a method according of the first aspect.
- the disorder may be a proliferative disease, for example, cancers such as lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma. Cancers of particular interest include ovarian, breast, prostate, and renal cancer, cholangiacarcinoma, and sarcoma.
- the proliferative disease may be characterised by the presence of a neoplasm comprising both KAAG1+ve and KAAG1-ve cells.
- the proliferative disease may be characterised by the presence of a neoplasm composed of KAAG1-ve neoplastic cells, optionally wherein the KAAG1-ve neoplastic cells are associated with KAAG1+ve non-neoplastic cells.
- the target neoplasm or neoplastic cells may be all or part of a solid tumour.
- Solid tumors may be neoplasms, including non-haematological cancers, comprising or composed of KAAG1+ve neoplastic cells.
- Solid tumors may be neoplasms, infiltrated with KAAG1+ve cells; such solid tumours may lack expression of KAAG1 (that is, comprise or be composed of KAAG1-ve neoplastic cells).
- the anti-KAAG1-ADC may be ADCT-901.
- the PARP inhibitor may be Olaparib (ABT-199), CEP-9722, BMN-673/talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib, 3-Aminobenzamide, or E7016.
- the PARP inhibitor is Olaparib (ABT-199).
- the individual may be human.
- the individual may have cancer, or may have been determined to have cancer.
- the individual may have, or have been determined to have, a KAAG1+ cancer or KAAG1+ tumour-associated non-tumour cells.
- the anti-KAAG1 ADC may be administered before the PARP inhibitor, simultaneous with the PARP inhibitor, or after the PARP inhibitor.
- the disclosed methods may comprise administering a further chemotherapeutic agent to the individual.
- the present disclosure provides an anti-KAAG1 ADC, or a composition comprising an anti-KAAG1 ADC, for use in a method of treatment as described herein.
- the present disclosure provides a PARP inhibitor, or a composition comprising a PARP inhibitor, for use in a method of treatment as described herein.
- the present disclosure provides for the use of an anti-KAAG1 ADC or an anti-PARP ADC in the manufacture of a medicament for treating a disorder in an individual, wherein the treatment comprises a method of treatment as described herein.
- the disclosure provides a first composition comprising an anti-KAAG1 ADC for use in a method of treating a disorder in an individual, wherein the treatment comprises administration of the first composition in combination with a second composition comprising a PARP inhibitor.
- a first composition comprising a PARP inhibitor for use in a method of treating a disorder in an individual, wherein the treatment comprises administration of the first composition in combination with a second composition comprising an anti-KAAG1 ADC.
- the disorder may be a proliferative disease, for example, cancers such as lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma.
- cancers of particular interest include ovarian, breast, prostate, and renal cancer, cholangiacarcinoma, and sarcoma.
- the anti-KAAG1-ADC may be ADCT-901.
- the PARP inhibitor may be Olaparib (ABT-199), CEP-9722, BMN-673/talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib, 3-Aminobenzamide, or E7016.
- the PARP inhibitor is Olaparib (ABT-199).
- the individual may be human.
- the individual may have cancer, or may have been determined to have cancer.
- the individual may have, or have been determined to have, a KAAG1+ cancer or KAAG1+ tumour-associated non-tumour cells.
- the first composition may be administered before the second composition, simultaneous with the second composition, or after the second composition.
- the treatment may comprise administering a further chemotherapeutic agent to the individual.
- the disclosure provides the use of an anti-KAAG1 ADC in the manufacture of a medicament for treating a disorder in an individual, wherein the medicament comprises an anti-KAAG1 ADC, and wherein the treatment comprises administration of the medicament in combination with a composition comprising PARP inhibitor.
- Also provided by this aspect is the use of PARP inhibitor in the manufacture of a medicament for treating a disorder in an individual, wherein the medicament comprises a PARP inhibitor, and wherein the treatment comprises administration of the medicament in combination with a composition comprising an anti-KAAG1 ADC.
- the disorder may be a proliferative disease, for example, cancers such as lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma. Cancers of particular interest include ovarian, breast, prostate, and renal cancer, cholangiacarcinoma, and sarcoma.
- the proliferative disease may be characterised by the presence of a neoplasm comprising both KAAG1+ve and KAAG1-ve cells.
- the proliferative disease may be characterised by the presence of a neoplasm composed of KAAG1-ve neoplastic cells, optionally wherein the KAAG1-ve neoplastic cells are associated with KAAG1+ve non-neoplastic cells.
- the target neoplasm or neoplastic cells may be all or part of a solid tumour.
- Solid tumors may be neoplasms comprising or composed of KAAG1+ve neoplastic cells.
- Solid tumors may be neoplasms infiltrated with KAAG1+ve cells; such solid tumours may lack expression of KAAG1 (that is, comprise or be composed of KAAG1-ve neoplastic cells).
- the anti-KAAG1-ADC may be ADCT-901.
- the PARP inhibitor may be Olaparib (ABT-199), CEP-9722, BMN-673/talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib, 3-Aminobenzamide, or E7016.
- the PARP inhibitor is Olaparib (ABT-199).
- the individual may be human.
- the individual may have cancer, or may have been determined to have cancer.
- the individual may have, or have been determined to have, a KAAG1+ cancer or KAAG1+ tumour-associated non-tumour cells.
- the medicament may be administered before the composition, simultaneous with the composition, or after the composition.
- the treatment may comprise administering a further chemotherapeutic agent to the individual.
- kits comprising: a first medicament comprising an anti-KAAG1 ADC; a package insert comprising instructions for administration of the first medicament according to a method of treatment as disclosed herein.
- the kit may further comprise a second medicament comprising a PARP inhibitor.
- kits comprising: a first medicament comprising an anti-KAAG1 ADC; a second medicament comprising a PARP inhibitor; and, optionally, a package insert comprising instructions for administration of the first medicament to an individual in combination with the second medicament for the treatment of a disorder.
- kits comprising a medicament comprising an anti-KAAG1 ADC and a package insert comprising instructions for administration of the medicament to an individual in combination with a composition comprising a PARP inhibitor for the treatment of a disorder.
- kits comprising a medicament comprising a PARP inhibitor and a package insert comprising instructions for administration of the medicament to an individual in combination with a composition comprising an anti-KAAG1 ADC for the treatment of a disorder.
- the disorder may be a proliferative disease, for example, cancers such as lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma.
- cancers of particular interest include ovarian, breast, prostate, and renal cancer, cholangiacarcinoma, and sarcoma.
- the proliferative disease may be characterised by the presence of a neoplasm comprising both KAAG1+ve and KAAG1-ve cells.
- the proliferative disease may be characterised by the presence of a neoplasm composed of KAAG1-ve neoplastic cells, optionally wherein the KAAG1-ve neoplastic cells are associated with KAAG1+ve non-neoplastic cells.
- the target neoplasm or neoplastic cells may be all or part of a solid tumour.
- Solid tumors may be neoplasms comprising or composed of KAAG1+ve neoplastic cells.
- Solid tumors may be neoplasms infiltrated with KAAG1+ve cells; such solid tumours may lack expression of KAAG1 (that is, comprise or be composed of KAAG1-ve neoplastic cells).
- the anti-KAAG1-ADC may be ADCT-901.
- the PARP inhibitor may be Olaparib (ABT-199), CEP-9722, BMN-673/talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib, 3-Aminobenzamide, or E7016.
- the PARP inhibitor is Olaparib (ABT-199).
- the individual may be human.
- the individual may have cancer, or may have been determined to have cancer.
- the individual may have, or have been determined to have, a KAAG1+ cancer or KAAG1+ tumour-associated non-tumour cells.
- the medicament or composition comprising the anti-KAAG1 ADC may be administered before the medicament or composition comprising the PARP inhibitor, simultaneous with the medicament or composition comprising the PARP inhibitor, or after the medicament or composition comprising the PARP inhibitor.
- the treatment may comprise administering a further chemotherapeutic agent to the individual.
- the disclosure provides a composition comprising an anti-KAAG1 ADC and a PARP inhibitor.
- Also provided in this aspect of the disclosure is a method of treating a disorder in an individual, the method comprising administering to the individual an effective amount of the composition comprising an anti-KAAG1 ADC and a PARP inhibitor.
- composition comprising an anti-KAAG1 ADC and a PARP inhibitor for use in a method of treating a disorder in an individual.
- compositions comprising an anti-KAAG1 ADC and a PARP inhibitor in the manufacture of a medicament for treating a disorder in an individual.
- kits comprising composition comprising an anti-KAAG1 ADC and a PARP inhibitor and a set of instructions for administration of the medicament to an individual for the treatment of a disorder.
- the disorder may be a proliferative disease, for example, cancers such as lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma.
- cancers of particular interest include ovarian, breast, prostate, and renal cancer, cholangiacarcinoma, and sarcoma.
- the proliferative disease may be characterised by the presence of a neoplasm comprising both KAAG1+ve and KAAG1-ve cells.
- the proliferative disease may be characterised by the presence of a neoplasm composed of KAAG1-ve neoplastic cells, optionally wherein the KAAG1-ve neoplastic cells are associated with KAAG1+ve non-neoplastic cells.
- the target neoplasm or neoplastic cells may be all or part of a solid tumour.
- Solid tumors may be neoplasms comprising or composed of KAAG1+ve neoplastic cells.
- Solid tumors may be neoplasms infiltrated with KAAG1+ve cells; such solid tumours may lack expression of KAAG1 (that is, comprise or be composed of KAAG1-ve neoplastic cells).
- the anti-KAAG1-ADC may be ADCT-901.
- the PARP inhibitor may be Olaparib (ABT-199), CEP-9722, BMN-673/talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib, 3-Aminobenzamide, or E7016.
- the PARP inhibitor is Olaparib (ABT-199).
- the individual may be human.
- the individual may have cancer, or may have been determined to have cancer.
- the individual may have, or have been determined to have, a KAAG1+ cancer or KAAG1+ tumour-associated non-tumour cells.
- the treatment may comprise administering a further chemotherapeutic agent to the individual.
- ADCs Antibody Drug Conjugates
- the present disclosure relates to the improved efficacy of combinations of an ADC and a PARP inhibitor.
- the ADC can deliver a drug to a target location.
- the target location is preferably a proliferative cell population.
- the antibody is an antibody for an antigen present on a proliferative cell population.
- the antigen is absent or present at a reduced level in a non-prol iterative cell population compared to the amount of antigen present in the proliferative cell population, for example a tumour cell population.
- the ADC may comprise a linker which may be cleaved so as to release the drug at the target location.
- the linker may be cleaved by an enzyme present at the target location.
- the disclosure particularly relates treatment with an anti-KAAG1 ADC disclosed in PCT/EP2020/065506, and as herein described.
- anti-KAAG1 ADCs disclosed in PCT/EP2020/065506, and as herein described.
- anti- KAAG1 -ADC refers to an ADC in which the antibody component is an anti-KAAG1 antibody and the drug component comprises a pyrrolobenzodiazepine (PBD), such as a PBD dimer.
- PBD dimers have been shown to form sequence selective, non-distorting and potently cytotoxic DNA interstrand cross-links in the minor groove of DNA. Typically therefore the PBD is able to bind to, and form interstrand cross-links in the minor groove of target cell DNA.
- the ADC may comprise a conjugate of formula L - (D L ) P , where D L is of formula I or II:
- L is an antibody (Ab) as defined below; when there is a double bond present between C2’ and C3’, R 12 is selected from the group consisting of: (ia) C 5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, carboxy, ester, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene; (ib) C 1-5 saturated aliphatic alkyl; (ic) C 3-6 saturated cycloalkyl; wherein each of R 21 , R 22 and R 23 are independently selected from H, C 1- 3 saturated alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R 12 group is no more than 5; (ie) , wherein one of R 25a and R 25b is H and the other is selected from: phenyl, which phenyl is optional
- R L1’ is a linker for connection to the antibody (Ab);
- R 11a is selected from OH, OR A , where R A is C 1-4 alkyl, and SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
- R 20 and R 21 either together form a double bond between the nitrogen and carbon atoms to which they are bound or;
- R 20 is selected from H and R C , where R C is a capping group;
- R 21 is selected from OH, OR A and SO z M; when there is a double bond present between C2 and C3,
- R 2 is selected from the group consisting of:
- the conjugate is selected from a conjugate of formula ConjA, ConjB, ConjC, ConjD and ConjE.
- the Conjugates comprise an antibody (Ab) as defined below covalently linked to at least one Drug unit by a Linker unit.
- the Ligand unit described more fully below, is a targeting agent that binds to a target moiety.
- the present disclosure also provides methods for the treatment of, for example, various cancers and autoimmune disease.
- the drug loading is represented by p, the number of drug molecules per antibody. Drug loading may range from 1 to 20 Drug units (D L ) per antibody.
- D L Drug units
- p represents the average drug loading of the Conjugates in the composition, and p ranges from 1 to 20.
- L 1 is enzyme cleavable, such as cathepsin cleavable.
- anti-KAAG1-ADC may include any embodiment described in PCT/EP2020/065506.
- a preferred embodiment is a conjugate having the structure: wherein the antibody comprises: (i) a VH domain having the sequence of SEQ ID NO.1 , and (ii) a VL domain having the sequence of SEQ ID NO.2.
- the antibody may comprise: (i) a VH domain having the sequence of SEQ ID NO.3, and (ii) a VL domain having the sequence of SEQ ID NO.4.
- the antibody is an antibody as described herein which has been modified (or further modified) as described in, for example, PCT/EP2020/065506.
- the antibody is a humanised, deimmunised or resurfaced version of an antibody disclosed herein.
- a preferred anti- KAAG1 -ADC for use with the aspects of the present disclosure is ADCT- 901.
- the antibody is an antibody that binds to KAAG1.
- the antibody comprises a VH domain having a VH CDR3 with the amino acid sequence of SEQ ID NO.7. In some embodiments the VH domain further comprises a VH CDR2 with the amino acid sequence of SEQ ID NO.6, and/or a VH CDR1 with the amino acid sequence of SEQ ID NO.5. In some embodiments the the antibody comprises a VH domain having a VH CDR1 with the amino acid sequence of SEQ ID NO.5, a VH CDR2 with the amino acid sequence of SEQ ID NO.6, and a VH CDR3 with the amino acid sequence of SEQ ID NO.7. In preferred embodiments the antibody comprises a VH domain having the sequence according to SEQ ID NO. 1.
- the antibody may further comprise a VL domain.
- the antibody comprises a VL domain having a VL CDR3 with the amino acid sequence of SEQ ID NO.10.
- the VL domain further comprises a VL CDR2 with the amino acid sequence of SEQ ID NO.9, and/or a VL CDR1 with the amino acid sequence of SEQ ID NO.8.
- the the antibody comprises a VL domain having a VL CDR1 with the amino acid sequence of SEQ ID NO.8, a VL CDR2 with the amino acid sequence of SEQ ID NO.9, and a VL CDR3 with the amino acid sequence of SEQ ID NO.10.
- the antibody comprises a VL domain having the sequence according to SEQ ID NO. 2, SEQ ID NO.13, or SEQ ID NO.15.
- the antibody comprises a VH domain and a VL domain.
- VH comprises the sequence of SEQ ID NO.1
- VL domain comprises the sequence of SEQ ID NO.2, SEQ ID NO.13, or SEQ ID NO.15.
- VH and VL domain(s) may pair so as to form an antibody antigen binding site that binds KAAG1.
- the antibody is an intact antibody comprising a VH domain paired with a VL domain, the VH and VL domains having sequences of SEQ ID NO.1 paired with SEQ ID NO.2, SEQ ID NO.13, or SEQ ID NO.15.
- the antibody has a VH domain comprising a VH CDR1 , a VH CDR2, and a VH CDR3, wherein the antibody comprises the CDR sequences of the VH domain having the sequence according to SEQ ID NO: 1.
- the antibody has a VL domain comprising a VL CDR1 , a VL CDR2, and a VL CDR3, wherein the antibody comprises the CDR sequences of the VL domain having the sequence according to SEQ ID NO: 2.
- the antibody comprises a heavy chain having the sequence of SEQ ID NO. 3 paired with a light chain having the sequence of SEQ ID NO.4, SEQ ID NO.14, or SEQ ID NO.16.
- the antibody is an intact antibody comprising two heavy chains having the sequence of SEQ ID NO.3, each paired with a light chain having the sequence of SEQ ID NO.4, SEQ ID NO.14, or SEQ ID NO.16.
- the antibody comprises a heavy chain having the sequence of SEQ ID NO. 11 paired with a light chain having the sequence of SEQ ID NO.4, SEQ ID NO.14, or SEQ ID NO.16.
- the antibody is an intact antibody comprising two heavy chains having the sequence of SEQ I D NO.11 , each paired with a light chain having the sequence of SEQ ID NO.4, SEQ ID NO.14, or SEQ ID NO.16.
- the antibody is an antibody as described herein which has been modified (or further modified) as described below.
- the antibody is a humanised, deimmunised or resurfaced version of an antibody disclosed herein. ADCT-901
- ADCT-901 is an antibody drug conjugate composed of a humanized antibody against human KAAG1 attached to a pyrrolobenzodiazepine (PBD) warhead via a cleavable linker.
- the mechanism of action of ADCT-901 depends on KAAG1 binding.
- the KAAG1 specific antibody targets the antibody drug conjugate (ADC) to cells expressing KAAG1.
- ADC antibody drug conjugate
- the ADC internalizes and is transported to the lysosome, where the protease sensitive linker is cleaved and free PBD dimer is released inside the target cell.
- the released PBD dimer inhibits transcription in a sequence-selective manner, due either to direct inhibition of RNA polymerase or inhibition of the interaction of associated transcription factors.
- the PBD dimer produces covalent crosslinks that do not distort the DNA double helix and which are not recognized by nucleotide excision repair factors, allowing for a longer effective period (Hartley 2011). t
- Ab represents Antibody 3A4 having the VH and VL sequences SEQ ID NO. 1 and SEQ ID NO. 2, respectively). It is synthesised as described in PCT/EP2020/065506 and typically has a DAR (Drug to Antibody Ratio) of about 2.2.
- DAR Drug to Antibody Ratio
- binds KAAG1 is used to mean the antibody binds KAAG1 with a higher affinity than a non-specific partner such as Bovine Serum Albumin (BSA, Genbank accession no. CAA76847, version no. CAA76847.1 Gl:3336842, record update date: Jan 7, 2011 02:30 PM).
- BSA Bovine Serum Albumin
- the antibody binds KAAG1 with an association constant (K a ) at least 2, 3, 4, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 10 4 , 10 5 or 10 6 -fold higher than the antibody’s association constant for BSA, when measured at physiological conditions.
- the antibodies of the disclosure can bind KAAG1 with a high affinity.
- the antibody can bind KAAG1 with a KD equal to or less than about 10 -6 M, such as 1 x 10 -6 , 10’ 7 , 10’ 8 , 10’ 9 , 10' 10 , 10’ 11 , 10’ 12 , 10- 13 or IQ- 14
- KAAG1 Kidney associated antigen 1
- the KAAG1 polypeptide corresponds to Genbank accession no. AAF23613, version no. AAF23613.1.
- the nucleic acid encoding KAAG1 polypeptide corresponds to Genbank accession no. AF181722, version no AF181722.1.
- the KAAG1 polypeptide has the sequence of SEQ ID NO.12.
- PARP-1 Poly (adenosine diphosphate [ADP]) ribose polymerase (PARP) are a family of enzymes involved in a wide range of cellular functions including DNA transcription, DNA damage response, genomic stability maintenance, cell cycle regulation, and cell death.
- PARP-1 is the most abundant and best characterised protein of this group. In oncology, its integral role in the repair of single-strand DNA breaks (SSBs) via the base excision repair (BER) pathway has been a focus of high interest and several PARP-1 inhibitors (PARPi) have been developed (including but not limited to Olaparib, CEP-9722, talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib) and are tested clinically. In cancer therapeutics, PARPi work predominantly by preventing the repair of DNA damage, ultimately causing cell death.
- SSBs single-strand DNA breaks
- BER base excision repair
- PARPi PARP-1 inhibitors
- PARPi work predominantly by preventing
- PARP is composed of four domains of interest: a DNA-binding domain, a caspase-cleaved domain, an auto-modification domain, and a catalytic domain.
- the DNA-binding domain is composed of two zinc finger motifs. In the presence of damaged DNA (base pair-excised), the DNA-binding domain will bind the DNA and induce a conformational shift. It has been shown that this binding occurs independent of the other domains. This is integral in a programmed cell death model based on caspase cleavage inhibition of PARP.
- the automodification domain is responsible for releasing the protein from the DNA after catalysis. Also, it plays an integral role in cleavage-induced inactivation.
- PARP is found in the cell nucleus. The main role is to detect and initiate an immediate cellular response to metabolic, chemical, or radiation-induced single-strand DNA breaks (SSB) by signalling the enzymatic machinery involved in the SSB repair. Once PARP detects a SSB, it binds to the DNA, undergoes a structural change, and begins the synthesis of a polymeric adenosine diphosphate ribose (poly (ADP-ribose) or PAR) chain, which acts as a signal for the other DNA-repairing enzymes.
- Target enzymes include DNA ligase III (Ligll I), DNA polymerase beta (poip), and scaffolding proteins such as X-ray crosscomplementing gene 1 (XRCC1). After repairing, the PAR chains are degraded via Poly(ADP-ribose) glycohydrolase (PARG).
- NAD+ is required as substrate for generating ADP-ribose monomers. It has been thought that overactivation of PARP may deplete the stores of cellular NAD+ and induce a progressive ATP depletion and necrotic cell death, since glucose oxidation is inhibited. But more recently it was suggested that inhibition of hexokinase activity leads to defects in glycolysis, (see Andrabi, PNAS 2014). Note below that PARP is inactivated by caspase-3 cleavage during programmed cell death. PARP enzymes are essential in a number of cellular functions, including expression of inflammatory genes: PARP1 is required for the induction of ICAM-1 gene expression by smooth muscle cells, in response to TNF.
- PBDs are a class of naturally occurring anti-tumor antibiotics found in Streptomyces. PBD dimers exert their cytotoxic mode of action via cross-linking of two strands of DNA, which results in the blockade of replication and tumor cell death. Importantly, the cross-links formed by PBD dimers are relatively non-distorting of the DNA structure, making them hidden to DNA repair mechanisms, which are often impaired in human tumors as opposed to normal tissues.
- PBD-based ADCs with PARPi including but not limited to Olaparib, CEP-9722, talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib
- PARPi including but not limited to Olaparib, CEP-9722, talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib
- a panel of solid tumor-derived cell lines will be treated with a range of concentration of each ADC and a PARPi.
- the in vitro cytotoxicity of the combinations (as determined by CellTiter-Glo® or MTS assays) will be measured. Cytotoxic synergy is calculated by transforming the cell viability data into fraction affected, and calculating the combination index using the CalcuSyn analysis program.
- PARP inhibitor means any chemical compound or biological molecule reduces PARP activity.
- samples or assays comprising a given, e.g., protein, gene, cell, or organism, are treated with a potential activating or inhibiting agent and are compared to control samples treated with an inactive control molecule. Control samples are assigned a relative activity value of 100%.
- Inhibition is achieved when the activity value relative to the control is about 90% or less, typically 85% or less, more typically 80% or less, most typically 75% or less, generally 70% or less, more generally 65% or less, most generally 60% or less, typically 55% or less, usually 50% or less, more usually 45% or less, most usually 40% or less, preferably 35% or less, more preferably 30% or less, still more preferably 25% or less, and most preferably less than 20%.
- PARPi suitable for use in the present disclosure include: a) Olaparib i. CAS Number ⁇ 763113-22-0
- talazoparib (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1 ,2,4- triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one d) Rucaparib i. CAS Number 283173-50-2
- Rucaparib 8-Fluoro-2- ⁇ 4-[(methylamino)methyl]phenyl ⁇ -1,3,4,5-tetrahydro-
- Veliparib 2-((R)-2-Methylpyrrolidin-2-yl)-1 H-benzimidazole-4-carboxamide g) Niraparib/MK-4827 i. CAS Number 1038915-60-4
- Niraparib 2-[4-[(3S)-3-Piperidyl]phenyl]indazole-7-carboxamide h) BGB-290
- PARP polypeptide is PARP1 , which corresponds to Genbank accession no. AAA60137, version no. AAA60137.1 , record update date: Jun 23, 2010 08:48 AM.
- the nucleic acid encoding PARP1 polypeptide corresponds to Genbank accession no. M18112, version no. M18112.1 , record update date: Jun 23, 2010 08:48 AM.
- PARP1 polypeptide corresponds to Uniprot/Swiss- Prot accession No. P09874.
- both the anti-KAAG1 ADC and PARP inhibitor when used as a single agent in isolation have demonstrated clinical utility - for example, in the treatment of cancer.
- combination of the anti-KAAG1 ADC and PARP inhibitor is expected to provide one or more of the following advantages over treatment with either anti-KAAG1 ADC or PARP inhibitor alone:
- Effective treatment of a broader range of cancers as used herein means that following treatment with the combination a complete response is observed with a greater range of recognised cancer types. That is, a complete response is seen from cancer types not previously reported to completely respond to either anti-KAAG1 ADC or PARP inhibitor alone.
- Effective treatment of a resistant, refractory, or relapsed forms as used herein means that following treatment with the combination a complete response is observed in individuals that are either partially or completely resistant or refractory to treatment with either anti-KAAG1 ADC or PARP inhibitor alone (for example, individuals who show no response or only partial response following treatment with either agent alone, or those with relapsed disorder).
- a complete response following treatment with the anti-KAAG1 ADC I PARP inhibitor combination is observed at least 10% of individuals that are either partially or completely resistant or refractory to treatment with either anti-KAAG1 ADC or PARP inhibitor alone.
- a complete response following treatment with the anti-KAAG1 ADC / PARP inhibitor combination is observed at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% of individuals that are either partially or completely resistant or refractory to treatment with either anti-KAAG1 ADC or PARP inhibitor alone.
- Increased response rate to treatment means that following treatment with the combination a complete response is observed in a greater proportion of individuals than is observed following treatment with either anti-KAAG1 ADC or PARP inhibitor alone.
- a complete response following treatment with the anti-KAAG1 ADC / PARP inhibitor combination is observed at least 10% of treated individuals.
- a complete response following treatment with the anti-KAAG1 ADC / PARP inhibitor combination is observed at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% of treated individuals.
- Increased durability of treatment means that average duration of complete response in individuals treated with the combination is longer than in individuals who achieve complete response following treatment with either anti-KAAG1 ADC or PARP inhibitor alone.
- the average duration of a complete response following treatment with the anti-KAAG1 ADC / PARP inhibitor combination is at least 6 months.
- the average duration of a complete response following treatment with the anti-KAAG1 ADC / PARP inhibitor combination is at least 12 months, at least 18 months, at least 24 months, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, at least 10 years, at least 15 years, or at least 20 years.
- Compplete response is used herein to mean the absence of any clinical evidence of disease in an individual. Evidence may be assessed using the appropriate methodology in the art, for example CT or PET scanning, or biopsy where appropriate.
- the number of doses required to achieve complete response may be one, two, three, four, five, ten or more. In some embodiments the individuals achieve complete response no more than a year after administration of the first dose, such as no more than 6 months, no more than 3 months, no more than a month, no more than a fortnight, or no more than a week after administration of the first dose.
- the therapies described herein include those with utility for anticancer activity.
- the therapies include an antibody conjugated, i.e. covalently attached by a linker, to a PBD drug moiety, i.e. toxin.
- a linker i.e. covalently attached by a linker
- the PBD drug has a cytotoxic effect.
- the biological activity of the PBD drug moiety is thus modulated by conjugation to an antibody.
- the antibody-drug conjugates (ADC) of the disclosure selectively deliver an effective dose of a cytotoxic agent to tumor tissue whereby greater selectivity, i.e. a lower efficacious dose, may be achieved.
- the present disclosure provides combined therapies comprising administering an anti-KAAG1 ADC which binds KAAG1 for use in therapy, wherein the method comprises selecting a subject based on expression of the target protein.
- the present disclosure provides a combined therapy with a label that specifies that the therapy is suitable for use with a subject determined to be suitable for such use.
- the label may specify that the therapy is suitable for use in a subject has expression of KAAG1 , such as overexpression of KAAG1.
- the label may specify that the subject has a particular type of cancer.
- a combined therapy as described herein for use in the treatment of a proliferative disease provides the use of a conjugate compound in the manufacture of a medicament for treating a proliferative disease.
- a conjugate compound in the manufacture of a medicament for treating a proliferative disease.
- assays which may conveniently be used to assess the activity offered by a particular compound are described below.
- proliferative disease pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo.
- proliferative conditions include, but are not limited to, benign, pre malignant, and malignant cellular proliferation, including but not limited to, neoplasms and tumours (e.g. histocytoma, glioma, astrocyoma, osteoma), cancers (e.g.
- lung cancer small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma), lymphomas, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g. of connective tissues), and atherosclerosis.
- Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g. bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.
- gastrointestinal including, e.g. bowel, colon
- breast mammary
- ovarian prostate
- liver hepatic
- kidney renal
- bladder pancreas
- brain and skin.
- disorders of particular interest include, but are not limited to cancers, including metastatic cancers and metastatic cancer cells, such as circulating tumour cells, which may be found circulating in body fluids such as blood or lymph.
- Cancers of particular interest include ovarian, breast, prostate, and renal cancer, cholangiacarcinoma, and sarcoma.
- KAAG1 KAAG1 antagonism will provide a clinical benefit.
- the proliferative disease may be characterised by the presence of a neoplasm comprising both KAAG1+ve and KAAG1-ve cells.
- the proliferative disease may be characterised by the presence of a neoplasm composed of KAAG1-ve neoplastic cells, optionally wherein the KAAG1-ve neoplastic cells are associated with KAAG1+ve non-neoplastic cells.
- the target neoplasm or neoplastic cells may be all or part of a solid tumour.
- Solid tumors may be neoplasms comprising or composed of KAAG1+ve neoplastic cells.
- Solid tumors may be neoplasms infiltrated with KAAG1+ve cells; such solid tumours may lack expression of KAAG1 (that is, comprise or be composed of KAAG1-ve neoplastic cells).
- the disease or disorder to be treated is a hyperproliferative disease such as cancer.
- cancer to be treated herein include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g.
- lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
- lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer,
- the subject has a proliferative disorder selected from lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma,
- the subject has a proliferative disease characterised by the presence of a neoplasm comprising both KAAG1+ve and KAAG1-ve cells.
- the proliferative disease may be characterised by the presence of a neoplasm composed of KAAG1-ve neoplastic cells, optionally wherein the KAAG1-ve neoplastic cells are associated with KAAG1+ve non-neoplastic cells.
- the target neoplasm or neoplastic cells may be all or part of a solid tumour.
- BRCA1 or BRCA2 deficient cells have defects in the repair of DNA double-strand breaks (DSBs) by the conservative, error-free pathway of homologous recombination (HR), leading to cellular sensitivity to specific DNA damaging agents (Tutt et al., ibid.).
- HR homologous recombination
- This mechanism has been exploited in the development of therapies to treat BRCA-associated cancers, including the demonstration that inhibition of the DNA repair enzyme Poly(ADP)-ribose Polymerase (PARP) is particularly selective for BRCA deficient cells (Farmer H, et al., Nature 2005; 434:917-21 ; Bryant HE, et al., Nature 2005; 434:913-7.).
- PARP Poly(ADP)-ribose Polymerase
- Example 1 The efficacy of the PARP inhibitor (PARPi) comprising combination therapies described herein is demonstrated in Example 1 , which shows synergistic in vivo therapeutic activity of the combination therapy in a BRCA1 mutant background.
- Example 3 further describes synergistic and additive in vitro therapeutic activity of the combination therapy in a wild type BRCA1 and BRCA2 background.
- the disorder treated by the combination therapies disclosed herein is a BRCA-associated cancer.
- the disorder treated by the combination therapies disclosed herein is a cancer that is not BRCA-associated.
- the BRCA-associated cancer has a mutation in a BRCA1 and/or BRCA2 gene.
- the mutation may be a spontaneous mutation or inherited mutation.
- the BRCA-associated cancer is characterised by cancer cells having a mutation in a BRCA1 and/or BRCA2 gene.
- the presence of a mutation in a BRCA gene may be determined by, for example, using direct sequencing, hybridisation to a probe, restriction fragment length polymorphism (RFLP) analysis, single-stranded conformation polymorphism (SSCP), PCR amplification of specific alleles, amplification of DNA target by PCR followed by a mini-sequencing assay, allelic discrimination during PCR, Genetic Bit Analysis, pyrosequencing, oligonucleotide ligation assay, analysis of melting curves or testing for a loss of heterozygosity (LOH).
- RFLP restriction fragment length polymorphism
- SSCP single-stranded conformation polymorphism
- PCR amplification of specific alleles amplification of DNA target by PCR followed by a mini-sequencing assay
- allelic discrimination during PCR allelic discrimination during PCR
- Genetic Bit Analysis pyrosequencing
- oligonucleotide ligation assay analysis of melting curves
- the BRCA-associated cancer is characterised by cancer cells exhibiting epigenetic inactivation of BRCA1 and/or BRCA2, for example by promoter hypermethylation.
- the epigenetic inactivation may be determined by, for example, methylation specific PCR to detect silencing of BRCA genes.
- the BRCA-associated cancer is characterised by cancer cells exhibiting loss of BRCA1 or BRCA2 function
- the BRCA-associated cancer may be characterised by defects or inactivation of BRCA1 and/or BRCA2 genes that are associated with the individual’s cancerous and non- cancerous cells. For example, if the individual had a germline mutation in BRCA1 and/or BRCA2.
- the BRCA-associated cancer may be characterised by defects or inactivation of BRCA1 and/or BRCA2 genes that are associated with the individual’s cancerous cells as opposed to the individual's non-cancerous cells, and in particular individuals whose tumours exhibit a defect in homologous recombination, the DNA repair mechanism controlled by BRCA1 and BRCA2.
- BRCA-associated cancer examples include female and male breast cancer, ovarian cancer, pancreatic cancer and prostate cancer (see, for example, J Mersch et al., Cancer. 2015 Jan 15; 121(2): 269-275.) Patient Selection
- the individuals are selected as suitable for treatment with the combined treatments before the treatments are administered.
- individuals who are considered suitable for treatment are those individuals who are expected to benefit from, or respond to, the treatment.
- Individuals may have, or be suspected of having, or be at risk of having cancer.
- Individuals may have received a diagnosis of cancer.
- individuals may have, or be suspected of having, or be at risk of having, ovarian, breast, prostate or renal cancer.
- individuals may have, or be suspected of having, or be at risk of having, a solid cancer that has tumour associated non-tumor cells that express KAAG1 , such as infiltrating cells that express KAAG1.
- subjects are selected on the basis of the amount or pattern of expression of KAAG1.
- the selection is based on expression of KAAG1 at the cell surface in a tissue or structure of interest. So, in some cases, subjects are selected on the basis they have, or are suspected of having, are at risk of having, or have received a diagnosis of a proliferative disease characterized by the presence of a neoplasm comprising or associated with cells having surface expression of KAAG1.
- the neoplasm may be composed of cells having surface expression of KAAG1.
- subjects are selected on the basis they have a neoplasm comprising both KAAG1+ve and KAAG1-ve cells.
- the neoplasm may be composed of KAAG1-ve neoplastic cells, optionally wherein the KAAG1-ve neoplastic cells are associated with KAAG1+ve non-neoplastic cells.
- the neoplasm or neoplastic cells may be all or part of a solid tumour.
- the solid tumour may be partially or wholly KAAG1-ve, and may be infiltrated with KAAG1+ve cells.
- expression of KAAG1 in a particular tissue of interest is determined. For example, in a sample of tumor tissue. In some cases, systemic expression of KAAG1 is determined. For example, in a sample of circulating fluid such as blood, plasma, serum or lymph.
- the subject is selected as suitable for treatment due to the presence of KAAG1 expression in a sample. In those cases, subjects without KAAG1 expression may be considered not suitable for treatment.
- the level of KAAG1 expression is used to select a subject as suitable for treatment. Where the level of expression of the target is above a threshold level, the subject is determined to be suitable for treatment.
- an subject is indicated as suitable for treatment if cells obtained from the tumour react with antibodies against KAAG1 as determined by IHC.
- a subject is determined to be suitable for treatment if at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more of all cells in the sample express KAAG1.
- a subject is determined to be suitable for treatment if at least at least 5% of the cells in the sample express KAAG1.
- the target is PARP.
- the selection is based on expression of PARP.
- the selection is based on levels of both KAAG1 at the cell surface and PARP.
- the presence of KAAG1 and/or in cells in the sample indicates that the individual is suitable for treatment with a combination comprising an anti-KAAG1 ADC and a PARP inhibitor.
- the amount of KAAG1 and/or expression must be above a threshold level to indicate that the individual is suitable for treatment.
- the observation that KAAG1 and/or localisation is altered in the sample as compared to a control indicates that the individual is suitable for treatment.
- an individual is indicated as suitable for treatment if cells obtained from lymph node or extra nodal sites react with antibodies against KAAG1 and/or as determined by IHC.
- a patient is determined to be suitable for treatment if at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more of all cells in the sample express KAAG1. In some aspects disclosed herein, a patient is determined to be suitable for treatment if at least at least 10% of the cells in the sample express KAAG1.
- a patient is determined to be suitable for treatment if at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more of all cells in the sample express. In some aspects disclosed herein, a patient is determined to be suitable for treatment if at least at least 10% of the cells in the sample express.
- the individual is selected as suitable for treatment based on their current or previous treatment regime. In some embodiments the individual is selected for treatment with the anti-KAAG1 ADC if the individual has been treated with a PARP inhibitor. In some embodiments the individual is selected for treatment with the anti-KAAG1 ADC if the individual is being treated with a PARP inhibitor. In some cases the individual is selected for treatment if they are refractory to treatment (or further treatment) with the PARP inhibitor. In some cases the PARP inhibitor may be Olaparib. In embodiments where the individual is undergoing, or has undergone, treatment with a PARP inhibitor, the anti-KAAG1 ADC may be administered in combination with a PARP inhibitor, or without continued administration of the PARP inhibitor.
- the anti-KAAG1 ADC is administered to the selected individual in combination with a PARP inhibitor. In some embodiments the anti-KAAG1 ADC is administered to the selected individual without continued administration of a PARP inhibitor.
- the PARP inhibitor is preferably Olaparib.
- the term ‘refractory to treatment (or further treatment) with the PARP inhibitor’ is used herein to mean that the disorder (such as cancer) does not respond, or has ceased to respond, to administration of the PARP inhibitor when administered as a monotherapy.
- the individual is selected for as suitable for treatment with the combination therapies disclosed herein based on their BRCA status.
- the individual is selected for treatment if they have a mutation in a BRCA1 and/or BRCA2 gene. In some embodiments the individual is selected for treatment if they have BRCA-associated cancer as described herein.
- the individual is selected for treatment if they do not have a mutation in a BRCA1 and/or BRCA2 gene. In some embodiments the individual is selected for treatment if they do not have a mutation in either of a BRCA1 and/or BRCA2 gene. In some embodiments the individual is selected for treatment if they have a cancer that is not a BRCA-associated cancer as described herein.
- the sample may comprise or may be derived from: a quantity of blood; a quantity of serum derived from the individual’s blood which may comprise the fluid portion of the blood obtained after removal of the fibrin clot and blood cells; a quantity of pancreatic juice; a tissue sample or biopsy; or cells isolated from said individual.
- a sample may be taken from any tissue or bodily fluid.
- the sample may include or may be derived from a tissue sample, biopsy, resection or isolated cells from said individual.
- the sample is a tissue sample.
- the sample may be a sample of tumor tissue, such as cancerous tumor tissue.
- the sample may have been obtained by a tumor biopsy.
- the sample is a lymphoid tissue sample, such as a lymphoid lesion sample or lymph node biopsy.
- the sample is a skin biopsy.
- the sample is taken from a bodily fluid, more preferably one that circulates through the body.
- the sample may be a blood sample or lymph sample.
- the sample is a urine sample or a saliva sample.
- the sample is a blood sample or blood-derived sample.
- the blood derived sample may be a selected fraction of a individual’s blood, e.g. a selected cell-containing fraction or a plasma or serum fraction.
- a selected cell-containing fraction may contain cell types of interest which may include white blood cells (WBC), particularly peripheral blood mononuclear cells (PBC) and/or granulocytes, and/or red blood cells (RBC).
- WBC white blood cells
- PBC peripheral blood mononuclear cells
- RBC red blood cells
- methods according to the present disclosure may involve detection of a first target polypeptide or nucleic acid in the blood, in white blood cells, peripheral blood mononuclear cells, granulocytes and/or red blood cells.
- the sample may be fresh or archival.
- archival tissue may be from the first diagnosis of an individual, or a biopsy at a relapse.
- the sample is a fresh biopsy.
- the first target polypeptide may be KAAG1.
- the individual may be an animal, mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a monotreme (e.g., duckbilled platypus), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an a
- the individual may be any of its forms of development, for example, a foetus.
- the individual is a human.
- the terms “subject”, “patient” and “individual” are used interchangeably herein.
- an individual has, or is suspected as having, or has been identified as being at risk of, cancer.
- the individual has already received a diagnosis of cancer.
- the individual may have received a diagnosis of a proliferative disease characterised by the presence of a neoplasm comprising both KAAG1+ve and KAAG1-ve cells.
- the proliferative disease may be characterised by the presence of a neoplasm composed of KAAG1-ve neoplastic cells, optionally wherein the KAAG1-ve neoplastic cells are associated with KAAG1+ve non-neoplastic cells.
- the individual has received a diagnosis of a solid tumour containing KAAG1+ expressing infiltrating cells.
- Solid tumors may be neoplasms, including non-haematological cancers, comprising or composed of KAAG1+ve neoplastic cells.
- Solid tumors may be neoplasms, including non- haematological cancers, infiltrated with KAAG1+ve cells; such solid tumours may lack expression of KAAG1 (that is, comprise or be composed of KAAG1-ve neoplastic cells).
- the Individual may be undergoing, or have undergone, a therapeutic treatment for that cancer.
- the subject may, or may not, have previously received ADCT-901 .
- the cancer is ovarian, breast, prostate or renal cancer.
- the Individual may be undergoing, or have undergone, treatment with a PARP inhibitor.
- the individual may be refractory to treatment (or further treatment) with the PARP inhibitor.
- the PARP inhibitor may be Olaparib.
- the anti-KAAG1 ADC may be administered in combination with a PARP inhibitor, or without continued administration of the PARP inhibitor.
- target expression in the individual is compared to target expression in a control.
- Controls are useful to support the validity of staining, and to identify experimental artefacts.
- control may be a reference sample or reference dataset.
- the reference may be a sample that has been previously obtained from an individual with a known degree of suitability.
- the reference may be a dataset obtained from analyzing a reference sample.
- Controls may be positive controls in which the target molecule is known to be present, or expressed at high level, or negative controls in which the target molecule is known to be absent or expressed at low level.
- Controls may be samples of tissue that are from individuals who are known to benefit from the treatment.
- the tissue may be of the same type as the sample being tested.
- a sample of tumor tissue from an individual may be compared to a control sample of tumor tissue from an individual who is known to be suitable for the treatment, such as an individual who has previously responded to the treatment.
- control may be a sample obtained from the same individual as the test sample, but from a tissue known to be healthy.
- a sample of cancerous tissue from an individual may be compared to a non-cancerous tissue sample.
- control is a cell culture sample.
- test sample is analyzed prior to incubation with an antibody to determine the level of background staining inherent to that sample.
- Isotype controls use an antibody of the same class as the target specific antibody, but are not immunoreactive with the sample. Such controls are useful for distinguishing non-specific interactions of the target specific antibody.
- the methods may include hematopathologist interpretation of morphology and immunohistochemistry, to ensure accurate interpretation of test results.
- the method may involve confirmation that the pattern of expression correlates with the expected pattern. For example, where the amount of KAAG1 and/or PARP expression is analyzed, the method may involve confirmation that in the test sample the expression is observed as membrane staining, with a cytoplasmic component. The method may involve confirmation that the ratio of target signal to noise is above a threshold level, thereby allowing clear discrimination between specific and non-specific background signals.
- treatment pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, regression of the condition, amelioration of the condition, and cure of the condition.
- Treatment as a prophylactic measure i.e., prophylaxis, prevention is also included.
- terapéuticaally-effective amount or “effective amount” as used herein, pertains to that amount of an active compound, or a material, composition or dosage from comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
- prophylactically-effective amount refers to that amount of an active compound, or a material, composition or dosage from comprising an active compound, which is effective for producing some desired prophylactic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
- a method of treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of an anti-KAAG1 ADC and a PARP inhibitor.
- therapeutically effective amount is an amount sufficient to show benefit to a subject. Such benefit may be at least amelioration of at least one symptom.
- the actual amount administered, and rate and timecourse of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage, is within the responsibility of general practitioners and other medical doctors.
- the subject may have been tested to determine their eligibility to receive the treatment according to the methods disclosed herein.
- the method of treatment may comprise a step of determining whether a subject is eligible for treatment, using a method disclosed herein.
- the anti-KAAG1 ADC comprises an anti-KAAG1 antibody.
- the anti-KAAG1 antibody may be 3A4 as disclosed herein.
- the ADC may comprise a drug which is a PBD dimer.
- the ADC may be an anti-KAAG1-ADC such as ADCT-901.
- the ADC may be an ADC disclosed in PCT/EP2020/065506.
- the PARP inhibitor may be Olaparib (ABT-199), CEP-9722, BMN-673/talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib, 3-Aminobenzamide, or E7016.
- the PARP inhibitor is Olaparib (ABT-199).
- the treatment may involve administration of the anti-KAAG1 ADC / PARP inhibitor combination alone or in further combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.
- An example method of treatment involves:
- a PARP inhibitor such as Olaparib in combination with the anti-KAAG1 ADC (for example, at the same time as the ADC, or after the ADC).
- treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g. drugs, such as chemotherapeutics); surgery; and radiation therapy.
- a “chemotherapeutic agent” is a chemical compound useful in the treatment of cancer, regardless of mechanism of action.
- Classes of chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, spindle poison plant alkaloids, cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors.
- Chemotherapeutic agents include compounds used in “targeted therapy” and conventional chemotherapy.
- chemotherapeutic agents include: Lenalidomide (REVLIMID®, Celgene), Vorinostat (ZOLINZA®, Merck), Panobinostat (FARYDAK®, Novartis), Mocetinostat (MGCD0103), Everolimus (ZORTRESS®, CERTICAN®, Novartis), Bendamustine (TREAKISYM®, RIBOMUSTIN®, LEVACT®, TREANDA®, Mundipharma International), erlotinib (TARCEVA®, Genentech/OSI Pharm.), docetaxel (TAXOTERE®, Sanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS No.
- gemcitabine Lilly
- PD- 0325901 CAS No. 391210-10-9, Pfizer
- cisplatin cis-diamine, dichloroplatinum(ll), CAS No. 15663-27-1
- carboplatin CAS No. 41575-94-4
- paclitaxel TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.J.
- trastuzumab HERCEPTIN®, Genentech
- temozolomide 4-methyl-5-oxo- 2,3,4,6,8-pentazabicyclo [4.3.0] nona-2,7,9-triene- 9- carboxamide, CAS No.
- tamoxifen (Z)-2-[4-(1 ,2-diphenylbut-1-enyl)phenoxy]-A/,/V-dimethylethanamine, NOLVADEX®, ISTUBAL®, VALODEX®), and doxorubicin (ADRIAMYCIN®), Akti-1/2, HPPD, and rapamycin.
- chemotherapeutic agents include: oxaliplatin (ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent (SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), XL-518 (Mek inhibitor, Exelixis, WO 2007/044515), ARRY-886 (Mek inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK 222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin (folinic acid), rapamycin (siroli
- calicheamicin calicheamicin gammal I, calicheamicin omegall (Angew Chem. Inti. Ed. Engl. (1994) 33:183-186); dynemicin, dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzi nostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin and
- chemotherapeutic agent include: (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole),
- SERMs
- chemotherapeutic agent examples include therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), pertuzumab (PERJETATM, OMNITARGTM, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), MDX-060 (Medarex) and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).
- therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), pertuzumab (PERJETATM, OMNITARGTM, 2C4, Genentech), trastuzum
- Humanized monoclonal antibodies with therapeutic potential as chemotherapeutic agents in combination with the conjugates of the disclosure include: alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab,
- compositions according to the present disclosure are preferably pharmaceutical compositions.
- Pharmaceutical compositions according to the present disclosure, and for use in accordance with the present disclosure may comprise, in addition to the active ingredient, i.e. a conjugate compound, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
- the precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g. cutaneous, subcutaneous, or intravenous.
- compositions for oral administration may be in tablet, capsule, powder or liquid form.
- a tablet may comprise a solid carrier or an adjuvant.
- Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
- a capsule may comprise a solid carrier such a gelatin.
- the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
- a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
- isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection.
- Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required.
- appropriate dosages of the anti-KAAG1 ADC and/or the PARP inhibitor, and compositions comprising these active elements can vary from subject to subject. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects.
- the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the subject.
- the amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
- the dosage of anti-KAAG1 ADC is determined by the expression of KAAG1 observed in a sample obtained from the subject.
- the level or localisation of expression of KAAG1 in the sample may be indicative that a higher or lower dose of anti-KAAG1 ADC is required.
- a high expression level of KAAG1 may indicate that a higher dose of anti-KAAG1 ADC would be suitable.
- a high expression level of KAAG1 may indicate the need for administration of another agent in addition to the anti-KAAG1 ADC.
- a high expression level of KAAG1 may indicate a more aggressive therapy.
- the dosage of the PARP inhibitor is determined by the expression of observed in a sample obtained from the subject.
- the level or localisation of expression of in the sample may be indicative that a higher or lower dose of PARP inhibitor is required.
- a high expression level of PARP may indicate that a higher dose of PARP inhibitor would be suitable.
- a high expression level of PARP may indicate the need for administration of another agent in addition to the PARP inhibitor.
- a high expression level of PARP may indicate a more aggressive therapy.
- Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
- a suitable dose of each active compound is in the range of about 100 ng to about 25 mg (more typically about 1 pg to about 10 mg) per kilogram body weight of the subject per day.
- the active compound is a salt, an ester, an amide, a prodrug, or the like
- the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
- each active compound is administered to a human subject according to the following dosage regime: about 100 mg, 3 times daily.
- each active compound is administered to a human subject according to the following dosage regime: about 150 mg, 2 times daily.
- each active compound is administered to a human subject according to the following dosage regime: about 200 mg, 2 times daily.
- each conjugate compound is administered to a human subject according to the following dosage regime: about 50 or about 75 mg, 3 or 4 times daily.
- each conjugate compound is administered to a human subject according to the following dosage regime: about 100 or about 125 mg, 2 times daily.
- the dosage amounts described above may apply to the conjugate (including the PBD moiety and the linker to the antibody) or to the effective amount of PBD compound provided, for example the amount of compound that is releasable after cleavage of the linker.
- the anti-KAAG1 ADC comprises an anti-KAAG1 antibody.
- the anti-KAAG1 antibody may be 3A4 as disclosed herein.
- the ADC may comprise a drug which is a PBD dimer.
- the ADC may be an anti-CDKAAG1-ADC such as ADCT-901.
- the ADC may be an ADC disclosed in PCT/EP2020/065506.
- the PARP inhibitor may be Olaparib (ABT-199), CEP-9722, BMN-673/talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib, 3-Aminobenzamide, or E7016.
- the PARP inhibitor is Olaparib (ABT-199).
- antibody herein is used in the broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), intact antibodies (also described as “full-length” antibodies) and antibody fragments, so long as they exhibit the desired biological activity, for example, the ability to bind KAAG1 (Miller et al (2003) Jour, of Immunology 170:4854-4861).
- Antibodies may be murine, human, humanized, chimeric, or derived from other species such as rabbit, goat, sheep, horse or camel.
- An antibody is a protein generated by the immune system that is capable of recognizing and binding to a specific antigen.
- a target antigen generally has numerous binding sites, also called epitopes, recognized by Complementarity Determining Regions (CDRs) on multiple antibodies.
- CDRs Complementarity Determining Regions
- An antibody may comprise a full-length immunoglobulin molecule or an immunologically active portion of a full-length immunoglobulin molecule, /.e., a molecule that contains an antigen binding site that immunospecifically binds an antigen of a target of interest or part thereof, such targets including but not limited to, cancer cell or cells that produce autoimmune antibodies associated with an autoimmune disease.
- the immunoglobulin can be of any type (e.g. IgG, IgE, IgM, IgD, and IgA), class (e.g. lgG1 , lgG2, lgG3, lgG4, lgA1 and lgA2) or subclass, or allotype (e.g.
- human G1m1 , G1m2, G1 m3, non-G1m1 [that, is any allotype other than G1m1], G1 m17, G2m23, G3m21 , G3m28, G3m11 , G3m5, G3m13, G3m14, G3m10, G3m15, G3m16, G3m6, G3m24, G3m26, G3m27, A2m1 , A2m2, Km1 , Km2 and Km3) of immunoglobulin molecule.
- the immunoglobulins can be derived from any species, including human, murine, or rabbit origin.
- Antibody fragments comprise a portion of a full length antibody, generally the antigen binding or variable region thereof.
- Examples of antibody fragments include Fab, Fab', F(ab')2, and scFv fragments; diabodies; linear antibodies; fragments produced by a Fab expression library, anti-idiotypic (anti-ld) antibodies, CDR (complementary determining region), and epitope-binding fragments of any of the above which immunospecifically bind to cancer cell antigens, viral antigens or microbial antigens, single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.
- the term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e. the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations which include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, the monoclonal antibodies are advantageous in that they may be synthesized uncontaminated by other antibodies.
- the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
- the monoclonal antibodies to be used in accordance with the present disclosure may be made by the hybridoma method first described by Kohler eta! (1975) Nature 256:495, or may be made by recombinant DNA methods (see, US 4816567).
- the monoclonal antibodies may also be isolated from phage antibody libraries using the techniques described in Clackson et al (1991) Nature, 352:624- 628; Marks et al (1991) J. Mol.
- the monoclonal antibodies herein specifically include “chimeric” antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (US 4816567; and Morrison et al (1984) Proc. Natl. Acad. Sci. USA, 81 :6851-6855).
- Chimeric antibodies include “primatized” antibodies comprising variable domain antigen-binding sequences derived from a non-human primate (e.g. Old World Monkey or Ape) and human constant region sequences.
- an “intact antibody” herein is one comprising VL and VH domains, as well as a light chain constant domain (CL) and heavy chain constant domains, CH1 , CH2 and CH3.
- the constant domains may be native sequence constant domains (e.g. human native sequence constant domains) or amino acid sequence variant thereof.
- the intact antibody may have one or more “effector functions” which refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody. Examples of antibody effector functions include C1q binding; complement dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; and down regulation of cell surface receptors such as B cell receptor and BCR.
- intact antibodies can be assigned to different “classes.” There are five major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into “subclasses” (isotypes), e.g., lgG1 , lgG2, lgG3, lgG4, IgA, and lgA2.
- the heavy-chain constant domains that correspond to the different classes of antibodies are called a, 6, e, Y, and , respectively.
- the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
- a method of selecting an individual as suitable for treatment with an anti-KAAG1 ADC wherein the individual is selected for treatment with the anti-KAAG1 ADC if the individual has been treated with a PARP inhibitor.
- a method of selecting an individual as suitable for treatment with an anti-KAAG1 ADC wherein the individual is selected for treatment with the anti-KAAG1 ADC if the individual is being treated with a PARP inhibitor.
- a method for treating a disorder in an individual comprising:
- a method for treating a disorder in an individual comprising administering to the individual an effective amount of an anti-KAAG1 ADC and PARP inhibitor.
- the treatment comprises administering the anti-KAAG1 ADC before the PARP inhibitor, simultaneous with the PARP inhibitor, or after the PARP inhibitor.
- the treatment further comprises administering a chemotherapeutic agent.
- the disorder is selected from the group comprising: lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, and sarcoma.
- the disorder is selected from the group comprising: ovarian, breast, prostate, renal cancer, cholangiacarcinoma, and sarcoma.
- the cancer is a BRCA-associated cancer.
- the PARP inhibitor is selected from the group consisting of: Olaparib (ABT-199), CEP-9722, BMN- 673/talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib, 3-Aminobenzamide, or E7016.
- the anti-KAAG1 ADC is a conjugate of formula L - (D L ) P , where D L is of formula I or II: wherein: L is an antibody (Ab) that binds to KAAG1; when there is a double bond present between C2’ and C3’, R 12 is selected from the group consisting of: (ia) C 5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, carboxy, ester, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene; (ib) C 1-5 saturated aliphatic alkyl; (ic) C 3-6 saturated cycloalkyl; wherein each of R 21 , R 22 and R 23 are independently selected from H, C 1- 3 saturated alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl, where the total number
- R L1’ is a linker for connection to the antibody (Ab);
- R 11a is selected from OH, OR A , where R A is C 1-4 alkyl, and SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
- R 20 and R 21 either together form a double bond between the nitrogen and carbon atoms to which they are bound or;
- R 20 is selected from H and R C , where R C is a capping group;
- R 21 is selected from OH, OR A and SO z M; when there is a double bond present between C2 and C3,
- R 2 is selected from the group consisting of:
- the anti-KAAG1 ADC comprises an antibody having a VH domain comprising a VH CDR1 , a VH CDR2, and a VH CDR3, wherein the antibody comprises the CDR sequences of the VH domain having the sequence according to SEQ ID NO: 1.
- the antibody comprises a VL domain comprising a VL CDR1 , a VL CDR2, and a VL CDR3, wherein the antibody comprises the CDR sequences of the VL domain having the sequence according to SEQ ID NO: 2.
- the anti-KAAG1 ADC comprises an antibody having a VH domain comprising a VH CDR1 with the amino acid sequence of SEQ ID NO.5, a VH CDR2 with the amino acid sequence of SEQ ID NO.6, and a VH CDR3 with the amino acid sequence of SEQ ID NO.7.
- the antibody comprises a VL domain comprising a VL CDR1 with the amino acid sequence of SEQ ID NO.8, a VL CDR2 with the amino acid sequence of SEQ ID NO.9, and a VL CDR3 with the amino acid sequence of SEQ ID NO.10.
- anti-KAAG1 ADC comprises an antibody having a VH domain having the sequence according to SEQ ID NO:
- anti-KAAG1 ADC comprises an antibody having a VL domain having the sequence according to SEQ ID NO:
- An anti-KAAG1 ADC for use in a method of treatment according to any one of paragraphs 4 to 47.
- a composition comprising an anti-KAAG1 ADC, for use in a method of treatment according to any one of paragraphs 4 to 47.
- a PARP inhibitor for use in a method of treatment according to any one of paragraphs 5 to 47.
- composition comprising a PARP inhibitor, for use in a method of treatment according to any one of paragraphs 5 to 47.
- a kit comprising: a first medicament comprising an anti-KAAG1 ADC; a package insert comprising instructions for administration of the first medicament according to the method of any one or paragraphs 4 to 47.
- kit according to paragraph 54 further comprising: A second medicament comprising a PARP inhibitor.
- Example 1 In vivo combination study of ADCT-901 and Olaparib in BRCA1 mut/BRCA2 wt, ovarian cancer PDX
- ADCT-901 (aka ADCxKAAGI) is an anti-KAAG1 antibody-drug conjugate (ADC) conjugated via a protease cleavable linker to SG3199, a highly cytotoxic DNA minor groove crosslinking pyrrolobenzodiazepine dimer (Flynn et al. Mol Cancer Ther 2016, and as described herein).
- the antibody employed 3A4 is a humanized version of the murine 3A4 antibody that was raised against human KAAG1 (see US9393392B2).
- Female Athymic Nude-Foxn1 nu were at least 6-8 weeks old on Day 0 of the study and had a body weight (BW) range of 19.3 to 29.1 g.
- ADCxKAAGI was administered intravenously as single dose at 0.5 mg/kg (0,5 mg/kg, qdx1) on day 0; olaparib was administered by oral gavage at 50 mg/kg every day for 28 days (50 mg/kg, qdx28) starting from day 0.
- both drugs were administered concomitantly on day 0 and then the subsequent doses of Olaparib were administered as per its monotherapy schedule.
- the dosing volume was 0.2 mL per 20 grams of body weight (10 mL/kg), and was scaled to the body weight of each individual animal.
- the study endpoint was when individual tumor volumes reached 1500 mm 3 or Day 60, whichever occurred first.
- This primary purpose of this study is to explore whether these agents can be safely combined, and if so, will identify the dose(s) and regimens appropriate for further study. The study will also assess whether each combination induces pharmacologic changes in tumor that would suggest potential clinical benefit.
- a combination may increase the response rate and durability of response compared with published data for treatment with single agent anti-KAAG1 ADC or PARP inhibitor.
- Each disease group may include a subset of patients previously treated with the PARP inhibitor to explore whether combination therapy might overcome resistance to PARP inhibitor therapy.
- it is not intended to apply specific molecular selection as the data available at present generally do not support excluding patients on the basis of approved molecular diagnostic tests.
- the RDE for already established f o r ADC (in ug/kg administered every three weeks) will be used for all patients in this study.
- a starting dose below the RDE will be used; the starting dose level will be one where patient benefit could still be demonstrated in study ADC1 , suggesting that patients enrolled at such dose level will gain at least some benefit by taking part.
- the RDE for already established f o r the PARP inhibitor (in ug/kg administered every three weeks) will be used for all patients in this study.
- a starting dose below the RDE will be used; the starting dose level will be one where patient benefit could still be demonstrated in study SA1 , suggesting that patients enrolled at such dose level will gain at least some benefit by taking part.
- the study is comprised of a dose escalation part followed by a dose expansion part.
- Dose escalation will start with reduced starting doses (compared to their respective recommended phase 2 or licensed dose levels), for both ADC and the PARP inhibitor, to guarantee patient safety. Starting doses will be 33% (or 50%) of the RDE for each compound. Subsequently, doses will be first escalated for the PARP inhibitor until the RDE or licensed dose has been reached, or a lower dose if necessary for tolerability reasons. Then, the dose for ADC will be escalated, until the RDE for combination treatment is reached.
- a perceived safe starting dose of 33% of the intended efficacious dose is proposed for both compounds, but this may need adaptation to lower or higher, as the individual risk profile for the combination may be.
- Compound 1 should be the compound for which an efficatious clinical dose has been firmly established (at 100%), and which is therefore aimed to be reached quickly in the trial patients by first escalating the dose of this compound.
- the dose combination is determined to be safe, it may be tested in additional patients to confirm the safety and tolerability at that dose level. Further tailoring of the dose of each compound may be conducted, and/or the regimen may be modified.
- the dose escalation of the combination will be guided by a Bayesian Logistic Regression Model (BLRM) based on any Dose Limiting Toxicities (DLTs) observed in the first (or first two, TBC) cycles of therapy.
- BLRM Bayesian Logistic Regression Model
- DLTs Dose Limiting Toxicities
- MTD maximum tolerated dose
- RDE recommended dose for expansion
- EWOC Escalation With Overdose Control
- the decisions on new dose combinations are made by the Investigators and sponsor study personnel in a dose escalation safety call (DESC) based upon the review of patient tolerability and safety information (including the BLRM summaries of DLT risk, if applicable) along with PK, PD and preliminary activity information available at the time of the decision.
- DSC dose escalation safety call
- the expansion part of the study may be initiated to further assess the safety, tolerability and preliminary efficacy.
- Dose Level 1 There will be a 24-hour observation before enrolling the second patient at Dose Level 1.
- the DLT observation period at each dose level is either 1 cycle (3 weeks) or 2 cycles (6 weeks) as mandated by the appropriate authorities for IO therapies, after which it will be determined whether to escalate to the next dose level, stay at the current dose level, or de- escalate to the previous dose level for the next cohort. There will be no de-escalation from Dose Level 1. Intrapatient dose escalation is not permitted.
- Dose escalation is not permitted unless 2 or more patients have complete DLT information through the first cycle in any given dose level. Dose escalation will be determined by using a mCRM with a target DLT rate of 30% and an equivalence interval of 20% to 35%, and with dose escalation-with-overdose-control (EWOC) and no dose skipping.
- EWOC dose escalation-with-overdose-control
- AEs adverse events
- laboratory values will be closely monitored for all enrolled patients in order to identify any DLTs.
- a single MTD/RDE will be defined; a disease-specific MTD/RDE will not be established.
- the mCRM will be implemented for DE under the oversight of a Dose Escalation Steering Committee (DESC).
- the DESC will confirm each escalating dose level after reviewing all available safety data. PK data from patients in that dose level and prior dose levels may also inform decision making.
- the DESC may halt dose escalation prior to determining the MTD based on emerging PK, PD, toxicity or response data.
- Additional patients may be included at any dose level to further assess the safety and tolerability if at least 1 patient in the study has achieved a partial response or better, or if further evaluation of PK or PD data is deemed necessary by the DESC to determine the RDE.
- Dose Escalation will be stopped after 3 cohorts (or at least 6 patients) are consecutively assigned to the same dose level. If the MTD is not reached, the recommended dose for expansion (RDE) will be determined. Prior to the determination of the MTD/RDE a minimum of 6 patients must have been treated with the combination.
- paired tumor biopsies will be obtained from patients during dose escalation. Analysis of these biopsies will contribute to a better understanding of the relationship between the dose and the pharmacodynamic activity of the combination.
- a DESC comprised of ADC Therapeutics and the investigators will review patient safety on an ongoing basis during the DE to determine if the dose escalation schedule prescribed by the mCRM warrants modification.
- PK and/or PD data may also inform decision making.
- Intermediate doses may be assigned after agreement between ADC Therapeutics and investigators.
- the DESC may continue to provide oversight during Part 2. No formal Data Safety Monitoring Board (DSMB) will be used.
- DSMB Data Safety Monitoring Board
- dose expansion part may begin.
- the main objective of the expansion part is to further assess the safety and tolerability of the study treatment at the MTD/RDE and to gain a preliminary understanding of the efficacy of the combination compared to historical single agent efficacy data.
- An important exploratory objective is to assess changes in the immune infiltrate in tumor in response to treatment. This will be assessed in paired tumor biopsies collected from patients, with a minimum of ten evaluable biopsy pairs (biopsy specimens must contain sufficient tumor for analysis) in patients treated at the MTD/RDE. If this is not feasible, collection of these biopsies may be stopped. A minimum of 10 to 20 patients are planned to be treated in each investigational arm,
- investigational arms will open, one per disease. A total of nine investigational arms may be run in the dose expansion. Should enrollment for any of these groups not be feasible, then enrollment to that group may be closed before the 10 to 20 patients target is met.
- the study will be conducted in adult patients with advanced Disease A, Disease B or Disease C as outlined above.
- the investigator or designee must ensure that only patients who meet all the following inclusion and none of the exclusion criteria are offered treatment in the study.
- TBC Patient must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patient must be willing to undergo a new tumor biopsy at baseline, and again during therapy on this study.
- Serum creatinine ⁇ 1.5 x ULN. If serum creatinine > 1.5, the creatinine clearance (calculated using Cockcroft-Gault formula, or measured) must be > 60 mL/min/1 ,73m2 for a patient to be eligible
- Total bilirubin > 1.5 x ULN except for patients with Gilbert's syndrome who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN
- ALT Alanine aminotransferase
- AST Aspartate aminotransferase
- LVEF Left Ventricular Ejection Fraction
- Testing is not mandatory to be eligible. Testing for HCV should be considered if the patient is at risk for having undiagnosed HCV (e.g. history of injection drug use). Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type. Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity, e.g.
- Active autoimmune disease, motor neuropathy considered of autoimmune origin, and other CNS autoimmune disease Patients requiring concomitant immunosuppressive agents or chronic treatment with corticoids except:
- ⁇ topical, inhaled, nasal and ophthalmic steroids are allowed Use of any live vaccines against infectious diseases (e.g. influenza, varicella, pneumococcus) within 4 weeks of initiation of study treatment (NB the use of live vaccines is not allowed through the whole duration of the study)
- Use of hematopoietic colony-stimulating growth factors e.g. G-CSF, GMCSF, M- CSF
- An erythroid stimulating agent is allowed as long as it was initiated at least 2 weeks prior to the first dose of study treatment.
- Major surgery within 2 weeks of the first dose of study treatment (NB mediastinoscopy, insertion of a central venous access device, or insertion of a feeding tube are not considered major surgery).
- Radiotherapy within 2 weeks of the first dose of study drug except for palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tun 1 or mass.
- patients must have remaining measurable disease that has not been irradiated Participation in an interventional, investigational study within 2 weeks of the first dose of study treatment. Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results.
- Sexually active males unless they use a condom during intercourse while taking drug and for 90 days after stopping study treatment and should not father a child in this period.
- a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.
- Pregnant or lactating women where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
- hCG levels may be above normal limits but with no pregnancy in the patient.
- there should be a repeat serum hCG test (with a non-rising result) and a vaginal/pelvic ultrasound to rule out pregnancy.
- Women of child-bearing potential defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during study treatment and for 90 days after the last any dose of study treatment.
- Highly effective contraception methods include:
- a dose-limiting toxicity is defined as any of the following events thought to be at least possibly related to ADC per investigator judgment that occurs during the 21-day DLT evaluation period. Toxicity that is clearly and directly related to the primary disease or to another etiology is excluded from this definition.
- a hematologic DLT is defined as:
- a non-hematologic DLT is defined as:
- Grade 3 or higher hypersensitivity/infusion-related reaction (regardless of premedication).
- a grade 3 hypersensitivity / infusion-related reaction that resolves within 8 hours after onset with appropriate clinical management does not qualify as a DLT.
- ⁇ LVEF decrease to ⁇ 40% or >20% decrease from baseline
- Grade 3 diarrhea nausea, or vomiting in the absence of premedication that responds to therapy and improves by at least 1 grade within 3 days for Grade 3 events or to ⁇ Grade 1 within 7 days.
- Patients who experience a DLT that resolves or stabilizes with appropriate medical management may continue treatment at the discretion of the investigator in consultation with the sponsor.
- Example 3 n vivo combination study of ADCT-901 and Olaparib in BRCA1 mut/BRCA2 wt, ovarian cancer PDX
- ADCxKAAGI was combined in SK-OV-3, MDA-MB-231 and SN12C cell lines with PARP inhibitor olaparib. Synergism was achieved in SK-OV-3 cell line combining ADCxKAAGI with olaparib. Additive effect was observed in MDA-MB-231 and SN12C cell lines.
- the in vitro data demonstrates that the combination of ADCxKAAGI and olaparib is beneficial in 3 cell lines that do not carry BRCA mutations.
- the data demonstrate conditions under which a synergistic therapeutic effect can be obtained. This is consistent with the therapeutic benefit observed in BRCA mutation carrying subjects (see Example 1) extending to subjects not carrying BRCA mutations.
- RRID cell accession identifier CVCL_0062 Cell line: SN12-C
- RRID cell accession identifier CVCL_0532 SEQUENCE LISTING PART OF THE DESCRIPTION
Abstract
The present disclosure relates to combination therapies for the treatment of pathological conditions, such as cancer. In particular, the present disclosure relates to combination therapies comprising treatment with an anti-KAAG1 Antibody Drug Conjugate and a PARP inhibitor.
Description
COMBINATION THERAPY COMPRISING ANTI-KAAG1 ANTIBODY DRUG CONJUGATE AND PARP INHIBITOR
EARLIER APPLICATION
This application claims priority from United Kingdom application number GB2012161.2, filed 5 August 2020. The priority applications is hereby incorporated by reference in its entirety and for any and all purposes as if fully set forth herein.
FIELD
The present disclosure relates to combination therapies for the treatment of pathological conditions, such as cancer. In particular, the present disclosure relates to combination therapies comprising treatment with an anti-KAAG1 Antibody Drug Conjugate (anti-KAAG1 ADC) and a PARP inhibitor.
BACKGROUND
Antibody Therapy
Antibody therapy has been established for the targeted treatment of subjects with cancer, immunological and angiogenic disorders (Carter, P. (2006) Nature Reviews Immunology 6:343-357). The use of antibody-drug conjugates (ADC), i.e. immunoconjugates, for the local delivery of cytotoxic or cytostatic agents, i.e. drugs to kill or inhibit tumour cells in the treatment of cancer, targets delivery of the drug moiety to tumours, and intracellular accumulation therein, whereas systemic administration of these unconjugated drug agents may result in unacceptable levels of toxicity to normal cells (Xie et al (2006) Expert. Opin. Biol. Ther. 6(3):281 -291 ; Kovtun et al (2006) Cancer Res. 66(6):3214-3121 ; Law et al (2006) Cancer Res. 66(4):2328-2337; Wu et al (2005) Nature Biotech. 23(9):1137-1145; Lambert J. (2005) Current Opin. in Pharmacol. 5:543-549; Hamann P. (2005) Expert Opin. Ther. Patents 15(9): 1087-1103; Payne, G. (2003) Cancer Cell 3:207-212; Trail et al (2003) Cancer Immunol. Immunother. 52:328-337; Syrigos and Epenetos (1999) Anticancer Research 19:605-614).
KAAG1
The KAAG1 peptide is encoded by the antisense strand of the RU2 gene (Van den Eynde et al., J Exp Med (1999) 190 (12): 1793-1800). This antisense transcript - ru2AS - is expressed as an 84 amino acid peptide in a high proportion of tumors of various histological types, including melanomas, sarcomas and colorectal carcinomas. It is absent in most normal tissues, but is expressed at lower levels in testis, kidney, urinary bladder, and liver. Quantification has indicated that expression levels in healthy tissue are in the region of 16-31 % (testis), 7-19% (kidney), or 6% (Bladder & liver) of those found in the LE9211-RCC carcinoma cell line.
In contrast, the expression product of the sense strand of the RU2 gene - ru2S - encodes a longer protein with potentially functional domains that is expressed at higher levels and in most tested tissues. This suggests a housekeeping function for RU2S, which is consistent with the presence of a CpG island in its promoter and in most of exon 1 .
Therefore, the KAAG1 antigen is not tumor specific, but corresponds to a self-antigen with restricted tissue distribution and expression in healthy tissue.
Therapeutic uses of anti-KAAG1 ADCs
The efficacy of an Antibody Drug Conjugate comprising an anti-KAAG1 antibody (an anti KAAG1-ADC) in the treatment of, for example, cancer has been established - see, for example, PCT/EP2020/065506.
Research continues to further improve the efficacy, tolerability, and clinical utility of anti- KAAG1 ADCs. To this end, the present authors have identified clinically advantageous combination therapies in which an anti-KAAG1 ADC is administered in combination with at least one PARP inhibitor.
SUMMARY
The present authors have determined that the administration of a combination of an anti-KAAG1 ADC and PARP inhibitor to an individual leads to unexpected clinical advantages. The present authors have further determined that administration of an anti- KAAG1 ADC to an individual that has either been treated with, or is being treated with, and PARP inhibitor leads to a synergistic increase in treatment efficacy.
Accordingly, in a first aspect the present disclosure provides a method of selecting an individual as suitable for treatment with an anti-KAAG1 ADC, wherein the individual is selected for treatment with the anti-KAAG1 ADC if the individual has been treated, or is being treated, with a PARP inhibitor. The individual may be selected for treatment if the individual is refractory to treatment, or further treatment, with the PARP inhibitor.
In another aspect, the present disclosure provides a method for treating a disorder in an individual, the method comprising selecting an individual as suitable for treatment by a method of the first aspect, and then administering to the individual an effective amount of the anti-KAAG1 ADC. The method of treatment may further comprise administering a PARP inhibitor in combination with the anti-KAAG1 ADC.
In another aspect the disclosure provides a method for treating a disorder in an individual, the method comprising administering to the individual an effective amount of an anti-KAAG1 ADC and PARP inhibitor. The individual may be selected for treatment according to a method according of the first aspect.
The disorder may be a proliferative disease, for example, cancers such as lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma. Cancers of particular interest include ovarian, breast, prostate, and renal cancer, cholangiacarcinoma, and sarcoma.
The proliferative disease may be characterised by the presence of a neoplasm comprising both KAAG1+ve and KAAG1-ve cells.
The proliferative disease may be characterised by the presence of a neoplasm composed of KAAG1-ve neoplastic cells, optionally wherein the KAAG1-ve neoplastic cells are associated with KAAG1+ve non-neoplastic cells.
The target neoplasm or neoplastic cells may be all or part of a solid tumour.
Solid tumors may be neoplasms, including non-haematological cancers, comprising or composed of KAAG1+ve neoplastic cells. Solid tumors may be neoplasms, infiltrated with KAAG1+ve cells; such solid tumours may lack expression of KAAG1 (that is, comprise or be composed of KAAG1-ve neoplastic cells).
The anti-KAAG1-ADC may be ADCT-901.
The PARP inhibitor may be Olaparib (ABT-199), CEP-9722, BMN-673/talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib, 3-Aminobenzamide, or E7016. Preferably the PARP inhibitor is Olaparib (ABT-199).
The individual may be human. The individual may have cancer, or may have been determined to have cancer. The individual may have, or have been determined to have, a KAAG1+ cancer or KAAG1+ tumour-associated non-tumour cells.
In the disclosed methods the anti-KAAG1 ADC may be administered before the PARP inhibitor, simultaneous with the PARP inhibitor, or after the PARP inhibitor. The disclosed methods may comprise administering a further chemotherapeutic agent to the individual.
In another aspect, the present disclosure provides an anti-KAAG1 ADC, or a composition comprising an anti-KAAG1 ADC, for use in a method of treatment as described herein.
In one aspect, the present disclosure provides a PARP inhibitor, or a composition comprising a PARP inhibitor, for use in a method of treatment as described herein.
In a further aspect, the present disclosure provides for the use of an anti-KAAG1 ADC or an anti-PARP ADC in the manufacture of a medicament for treating a disorder in an individual, wherein the treatment comprises a method of treatment as described herein.
In another aspect, the disclosure provides a first composition comprising an anti-KAAG1 ADC for use in a method of treating a disorder in an individual, wherein the treatment comprises administration of the first composition in combination with a second composition comprising a PARP inhibitor.
Also provided by this aspect is a first composition comprising a PARP inhibitor for use in a method of treating a disorder in an individual, wherein the treatment comprises administration of the first composition in combination with a second composition comprising an anti-KAAG1 ADC.
The disorder may be a proliferative disease, for example, cancers such as lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma. Cancers of particular interest include ovarian, breast, prostate, and renal cancer, cholangiacarcinoma, and sarcoma.
The anti-KAAG1-ADC may be ADCT-901.
The PARP inhibitor may be Olaparib (ABT-199), CEP-9722, BMN-673/talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib, 3-Aminobenzamide, or E7016. Preferably the PARP inhibitor is Olaparib (ABT-199).
The individual may be human. The individual may have cancer, or may have been determined to have cancer. The individual may have, or have been determined to have, a KAAG1+ cancer or KAAG1+ tumour-associated non-tumour cells.
The first composition may be administered before the second composition, simultaneous with the second composition, or after the second composition. The treatment may comprise administering a further chemotherapeutic agent to the individual.
In a further aspect, the disclosure provides the use of an anti-KAAG1 ADC in the manufacture of a medicament for treating a disorder in an individual, wherein the medicament comprises an anti-KAAG1 ADC, and wherein the treatment comprises administration of the medicament in combination with a composition comprising PARP inhibitor.
Also provided by this aspect is the use of PARP inhibitor in the manufacture of a medicament for treating a disorder in an individual, wherein the medicament comprises a PARP inhibitor, and wherein the treatment comprises administration of the medicament in combination with a composition comprising an anti-KAAG1 ADC.
The disorder may be a proliferative disease, for example, cancers such as lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma. Cancers of particular interest include ovarian, breast, prostate, and renal cancer, cholangiacarcinoma, and sarcoma.
The proliferative disease may be characterised by the presence of a neoplasm comprising both KAAG1+ve and KAAG1-ve cells.
The proliferative disease may be characterised by the presence of a neoplasm composed of KAAG1-ve neoplastic cells, optionally wherein the KAAG1-ve neoplastic cells are associated with KAAG1+ve non-neoplastic cells.
The target neoplasm or neoplastic cells may be all or part of a solid tumour.
Solid tumors may be neoplasms comprising or composed of KAAG1+ve neoplastic cells. Solid tumors may be neoplasms infiltrated with KAAG1+ve cells; such solid tumours may lack expression of KAAG1 (that is, comprise or be composed of KAAG1-ve neoplastic cells).
The anti-KAAG1-ADC may be ADCT-901.
The PARP inhibitor may be Olaparib (ABT-199), CEP-9722, BMN-673/talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib, 3-Aminobenzamide, or E7016. Preferably the PARP inhibitor is Olaparib (ABT-199).
The individual may be human. The individual may have cancer, or may have been determined to have cancer. The individual may have, or have been determined to have, a KAAG1+ cancer or KAAG1+ tumour-associated non-tumour cells.
The medicament may be administered before the composition, simultaneous with the composition, or after the composition. The treatment may comprise administering a further chemotherapeutic agent to the individual.
Another aspect of the disclosure provides a kit comprising: a first medicament comprising an anti-KAAG1 ADC; a package insert comprising instructions for administration of the first medicament according to a method of treatment as disclosed herein. The kit may further comprise a second medicament comprising a PARP inhibitor.
Another aspect of the disclosure provides a kit comprising: a first medicament comprising an anti-KAAG1 ADC; a second medicament comprising a PARP inhibitor; and, optionally, a package insert comprising instructions for administration of the first medicament to an individual in combination with the second medicament for the treatment of a disorder.
Also provided by this aspect is a kit comprising a medicament comprising an anti-KAAG1 ADC and a package insert comprising instructions for administration of the medicament to
an individual in combination with a composition comprising a PARP inhibitor for the treatment of a disorder.
Further provided by this aspect is a kit comprising a medicament comprising a PARP inhibitor and a package insert comprising instructions for administration of the medicament to an individual in combination with a composition comprising an anti-KAAG1 ADC for the treatment of a disorder.
The disorder may be a proliferative disease, for example, cancers such as lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma. Cancers of particular interest include ovarian, breast, prostate, and renal cancer, cholangiacarcinoma, and sarcoma.
The proliferative disease may be characterised by the presence of a neoplasm comprising both KAAG1+ve and KAAG1-ve cells.
The proliferative disease may be characterised by the presence of a neoplasm composed of KAAG1-ve neoplastic cells, optionally wherein the KAAG1-ve neoplastic cells are associated with KAAG1+ve non-neoplastic cells.
The target neoplasm or neoplastic cells may be all or part of a solid tumour.
Solid tumors may be neoplasms comprising or composed of KAAG1+ve neoplastic cells. Solid tumors may be neoplasms infiltrated with KAAG1+ve cells; such solid tumours may lack expression of KAAG1 (that is, comprise or be composed of KAAG1-ve neoplastic cells).
The anti-KAAG1-ADC may be ADCT-901.
The PARP inhibitor may be Olaparib (ABT-199), CEP-9722, BMN-673/talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib, 3-Aminobenzamide, or E7016. Preferably the PARP inhibitor is Olaparib (ABT-199).
The individual may be human. The individual may have cancer, or may have been determined to have cancer. The individual may have, or have been determined to have, a KAAG1+ cancer or KAAG1+ tumour-associated non-tumour cells.
The medicament or composition comprising the anti-KAAG1 ADC may be administered before the medicament or composition comprising the PARP inhibitor, simultaneous with the medicament or composition comprising the PARP inhibitor, or after the medicament or composition comprising the PARP inhibitor. The treatment may comprise administering a further chemotherapeutic agent to the individual.
In a yet further aspect, the disclosure provides a composition comprising an anti-KAAG1 ADC and a PARP inhibitor.
Also provided in this aspect of the disclosure is a method of treating a disorder in an individual, the method comprising administering to the individual an effective amount of the composition comprising an anti-KAAG1 ADC and a PARP inhibitor.
Also provided in this aspect of the disclosure is a composition comprising an anti-KAAG1 ADC and a PARP inhibitor for use in a method of treating a disorder in an individual.
Also provided in this aspect of the disclosure is the use of a composition comprising an anti-KAAG1 ADC and a PARP inhibitor in the manufacture of a medicament for treating a disorder in an individual.
Also provided in this aspect of the disclosure is a kit comprising composition comprising an anti-KAAG1 ADC and a PARP inhibitor and a set of instructions for administration of the medicament to an individual for the treatment of a disorder.
The disorder may be a proliferative disease, for example, cancers such as lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, and melanoma. Cancers of particular interest include ovarian, breast, prostate, and renal cancer, cholangiacarcinoma, and sarcoma.
The proliferative disease may be characterised by the presence of a neoplasm comprising both KAAG1+ve and KAAG1-ve cells.
The proliferative disease may be characterised by the presence of a neoplasm composed of KAAG1-ve neoplastic cells, optionally wherein the KAAG1-ve neoplastic cells are associated with KAAG1+ve non-neoplastic cells.
The target neoplasm or neoplastic cells may be all or part of a solid tumour.
Solid tumors may be neoplasms comprising or composed of KAAG1+ve neoplastic cells. Solid tumors may be neoplasms infiltrated with KAAG1+ve cells; such solid tumours may lack expression of KAAG1 (that is, comprise or be composed of KAAG1-ve neoplastic cells).
The anti-KAAG1-ADC may be ADCT-901.
The PARP inhibitor may be Olaparib (ABT-199), CEP-9722, BMN-673/talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib, 3-Aminobenzamide, or E7016. Preferably the PARP inhibitor is Olaparib (ABT-199).
The individual may be human. The individual may have cancer, or may have been determined to have cancer. The individual may have, or have been determined to have, a KAAG1+ cancer or KAAG1+ tumour-associated non-tumour cells.
The treatment may comprise administering a further chemotherapeutic agent to the individual.
DETAILED DESCRIPTION
Antibody Drug Conjugates (ADCs)
The present disclosure relates to the improved efficacy of combinations of an ADC and a PARP inhibitor.
The ADC can deliver a drug to a target location. The target location is preferably a proliferative cell population. The antibody is an antibody for an antigen present on a proliferative cell population. In one aspect the antigen is absent or present at a reduced level in a non-prol iterative cell population compared to the amount of antigen present in the proliferative cell population, for example a tumour cell population.
The ADC may comprise a linker which may be cleaved so as to release the drug at the target location. The linker may be cleaved by an enzyme present at the target location.
The disclosure particularly relates treatment with an anti-KAAG1 ADC disclosed in PCT/EP2020/065506, and as herein described. anti-KAAG1 ADCs
As used herein, the term “anti- KAAG1 -ADC” refers to an ADC in which the antibody component is an anti-KAAG1 antibody and the drug component comprises a pyrrolobenzodiazepine (PBD), such as a PBD dimer. PBD dimers have been shown to form sequence selective, non-distorting and potently cytotoxic DNA interstrand cross-links in the minor groove of DNA. Typically therefore the PBD is able to bind to, and form interstrand cross-links in the minor groove of target cell DNA.
The ADC may comprise a conjugate of formula L - (DL)P, where DL is of formula I or II:
wherein: L is an antibody (Ab) as defined below; when there is a double bond present between C2’ and C3’, R12 is selected from the group consisting of: (ia) C5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, carboxy, ester, C1-7 alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene; (ib) C1-5 saturated aliphatic alkyl; (ic) C3-6 saturated cycloalkyl;
wherein each of R21, R22 and R23 are independently selected from H, C1- 3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R12 group is no more than 5; (ie)
, wherein one of R25a and R25b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and (if)
, where R 24 is selected from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; when there is a single bond present between C2’ and C3’, R12 is
, where R 26a and R 26b are independently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group
selected from C1-4 alkyl amido and C1-4 alkyl ester; or, when one of R26a and R26b is H, the other is selected from nitrile and a C1-4 alkyl ester; R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR’, nitro, Me3Sn and halo; where R and R’ are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR’, nitro, Me3Sn and halo; R″ is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, NRN2 (where RN2 is H or C1-4 alkyl), and/or aromatic rings, e.g. benzene or pyridine; Y and Y’ are selected from O, S, or NH; R6’, R7’, R9’ are selected from the same groups as R6, R7 and R9 respectively; [Formula I] RL1’ is a linker for connection to the antibody (Ab); R11a is selected from OH, ORA, where RA is C1-4 alkyl, and SOzM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; R20 and R21 either together form a double bond between the nitrogen and carbon atoms to which they are bound or; R20 is selected from H and RC, where RC is a capping group; R21 is selected from OH, ORA and SOzM; when there is a double bond present between C2 and C3, R2 is selected from the group consisting of: (ia) C5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, carboxy, ester, C1-7 alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene; (ib) C1-5 saturated aliphatic alkyl; (ic) C3-6 saturated cycloalkyl;
, wherein each of R11, R12 and R13 are independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R2 group is no more than 5; (ie)
, wherein one of R15a and R15b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and (if)
, where R14 is selected from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; when there is a single bond present between C2 and C3,
R2 is
, where R16a and R16b are independently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester; or, when one of R16a and R16b is H, the other is selected from nitrile and a C1-4 alkyl ester; [Formula II] R22 is of formula IIIa, formula IIIb or formula IIIc:
where A is a C5-7 aryl group, and either (i) Q1 is a single bond, and Q2 is selected from a single bond and -Z-(CH2)n-, where Z is selected from a single bond, O, S and NH and n is from 1 to 3; or (ii) Q1 is -CH=CH-, and Q2 is a single bond;
RC1, RC2 and RC3 are independently selected from H and unsubstituted C1-2 alkyl;
where Q is selected from O-RL2’, S-RL2’ and NRN-RL2’, and RN is selected from H, methyl and ethyl X is selected from the group comprising: O-RL2’, S-RL2’, CO2-RL2’, CO-RL2’, NH-C(=O)-RL2’, NHNH-RL2’, CONHNH-RL2’,
, NRNRL2’, wherein RN is selected from the group comprising H and C1-4 alkyl; RL2’ is a linker for connection to the antibody (Ab); R10 and R11 either together form a double bond between the nitrogen and carbon atoms to which they are bound or; R10 is H and R11 is selected from OH, ORA and SOzM; R30 and R31 either together form a double bond between the nitrogen and carbon atoms to which they are bound or; R30 is H and R31 is selected from OH, ORA and SOzM. In some embodiments, the conjugate is not: ConjA
n other embodiments, it may be preferred that the conjugate is selected from a conjugate of formula ConjA, ConjB, ConjC, ConjD and ConjE.
The subscript p in the formula I is an integer of from 1 to 20. Accordingly, the Conjugates comprise an antibody (Ab) as defined below covalently linked to at least one Drug unit by a Linker unit. The Ligand unit, described more fully below, is a targeting agent that binds to a target moiety. Accordingly, the present disclosure also provides methods for the treatment of, for example, various cancers and autoimmune disease. The drug loading is represented by p, the number of drug molecules per antibody. Drug loading may range from 1 to 20 Drug units (DL) per antibody. For compositions, p represents the average drug loading of the Conjugates in the composition, and p ranges from 1 to 20.
In some embodiments L-RL1’ or L-RL2’ is a group:
where the asterisk indicates the point of attachment to the PBD, Ab is the antibody, L1 is a cleavable linker, A is a connecting group connecting L1 to the antibody, L2 is a covalent bond or together with -OC(=O)- forms a self-immolative linker.
In some of these embodiments, L1 is enzyme cleavable, such as cathepsin cleavable.
It has previously been shown that such ADCs are useful in the treatment of KAAG1 expressing cancers (see, for example, PCT/EP2020/065506, which is incorporated by reference herein in its entirety).
The term anti-KAAG1-ADC may include any embodiment described in PCT/EP2020/065506.
A preferred embodiment is a conjugate having the structure:
wherein the antibody comprises: (i) a VH domain having the sequence of SEQ ID NO.1 , and (ii) a VL domain having the sequence of SEQ ID NO.2.
The antibody may comprise: (i) a VH domain having the sequence of SEQ ID NO.3, and (ii) a VL domain having the sequence of SEQ ID NO.4.
In an aspect the antibody is an antibody as described herein which has been modified (or further modified) as described in, for example, PCT/EP2020/065506. In some embodiments the antibody is a humanised, deimmunised or resurfaced version of an antibody disclosed herein.
A preferred anti- KAAG1 -ADC for use with the aspects of the present disclosure is ADCT- 901.
Antibody
In one aspect the antibody is an antibody that binds to KAAG1.
Antibody 3A4
In some embodiments the antibody comprises a VH domain having a VH CDR3 with the amino acid sequence of SEQ ID NO.7. In some embodiments the VH domain further comprises a VH CDR2 with the amino acid sequence of SEQ ID NO.6, and/or a VH CDR1 with the amino acid sequence of SEQ ID NO.5. In some embodiments the the antibody comprises a VH domain having a VH CDR1 with the amino acid sequence of SEQ ID NO.5, a VH CDR2 with the amino acid sequence of SEQ ID NO.6, and a VH CDR3 with the amino acid sequence of SEQ ID NO.7. In preferred embodiments the antibody comprises a VH domain having the sequence according to SEQ ID NO. 1.
The antibody may further comprise a VL domain. In some embodiments the antibody comprises a VL domain having a VL CDR3 with the amino acid sequence of SEQ ID NO.10.
In some embodiments the VL domain further comprises a VL CDR2 with the amino acid sequence of SEQ ID NO.9, and/or a VL CDR1 with the amino acid sequence of SEQ ID NO.8. In some embodiments the the antibody comprises a VL domain having a VL CDR1 with the amino acid sequence of SEQ ID NO.8, a VL CDR2 with the amino acid sequence of SEQ ID NO.9, and a VL CDR3 with the amino acid sequence of SEQ ID NO.10. In preferred embodiments the antibody comprises a VL domain having the sequence according to SEQ ID NO. 2, SEQ ID NO.13, or SEQ ID NO.15.
In preferred embodiments the antibody comprises a VH domain and a VL domain. Preferably the VH comprises the sequence of SEQ ID NO.1 and the VL domain comprises the sequence of SEQ ID NO.2, SEQ ID NO.13, or SEQ ID NO.15.
The VH and VL domain(s) may pair so as to form an antibody antigen binding site that binds KAAG1.
In some embodiments the antibody is an intact antibody comprising a VH domain paired with a VL domain, the VH and VL domains having sequences of SEQ ID NO.1 paired with SEQ ID NO.2, SEQ ID NO.13, or SEQ ID NO.15.
In some embodiments the antibody has a VH domain comprising a VH CDR1 , a VH CDR2, and a VH CDR3, wherein the antibody comprises the CDR sequences of the VH domain having the sequence according to SEQ ID NO: 1. In some embodiments the antibody has a VL domain comprising a VL CDR1 , a VL CDR2, and a VL CDR3, wherein the antibody comprises the CDR sequences of the VL domain having the sequence according to SEQ ID NO: 2.
In some embodiments the antibody comprises a heavy chain having the sequence of SEQ ID NO. 3 paired with a light chain having the sequence of SEQ ID NO.4, SEQ ID NO.14, or SEQ ID NO.16. In some embodiments the antibody is an intact antibody comprising two heavy chains having the sequence of SEQ ID NO.3, each paired with a light chain having the sequence of SEQ ID NO.4, SEQ ID NO.14, or SEQ ID NO.16.
In some embodiments the antibody comprises a heavy chain having the sequence of SEQ ID NO. 11 paired with a light chain having the sequence of SEQ ID NO.4, SEQ ID NO.14, or SEQ ID NO.16. In some embodiments the antibody is an intact antibody comprising two heavy chains having the sequence of SEQ I D NO.11 , each paired with a light chain having the sequence of SEQ ID NO.4, SEQ ID NO.14, or SEQ ID NO.16.
In one aspect the antibody is an antibody as described herein which has been modified (or further modified) as described below. In some embodiments the antibody is a humanised, deimmunised or resurfaced version of an antibody disclosed herein.
ADCT-901
ADCT-901 is an antibody drug conjugate composed of a humanized antibody against human KAAG1 attached to a pyrrolobenzodiazepine (PBD) warhead via a cleavable linker. The mechanism of action of ADCT-901 depends on KAAG1 binding. The KAAG1 specific antibody targets the antibody drug conjugate (ADC) to cells expressing KAAG1. Upon binding, the ADC internalizes and is transported to the lysosome, where the protease sensitive linker is cleaved and free PBD dimer is released inside the target cell. The released PBD dimer inhibits transcription in a sequence-selective manner, due either to direct inhibition of RNA polymerase or inhibition of the interaction of associated transcription factors. The PBD dimer produces covalent crosslinks that do not distort the DNA double helix and which are not recognized by nucleotide excision repair factors, allowing for a longer effective period (Hartley 2011). t has the chemical structure:
Ab represents Antibody 3A4 having the VH and VL sequences SEQ ID NO. 1 and SEQ ID NO. 2, respectively). It is synthesised as described in PCT/EP2020/065506 and typically has a DAR (Drug to Antibody Ratio) of about 2.2.
KAAG1 binding
As used herein, “binds KAAG1” is used to mean the antibody binds KAAG1 with a higher affinity than a non-specific partner such as Bovine Serum Albumin (BSA, Genbank accession no. CAA76847, version no. CAA76847.1 Gl:3336842, record update date: Jan 7, 2011 02:30 PM). In some embodiments the antibody binds KAAG1 with an association constant (Ka) at least 2, 3, 4, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 104, 105 or 106-fold higher than the antibody’s association constant for BSA, when measured at physiological conditions. The antibodies of the disclosure can bind KAAG1 with a high affinity. For example, in some embodiments the antibody can bind KAAG1 with a KD equal to or less than about 10-6 M, such as 1 x 10-6, 10’7, 10’8, 10’9, 10'10, 10’11, 10’12, 10-13 or IQ- 14
KAAG1 (Kidney associated antigen 1) is expressed in testis and kidney, and, at lower levels, in urinary bladder and liver. It is expressed by a high proportion of tumors of various histologic origin, including melanomas, sarcomas and colorectal carcinomas. In some
embodiments, the KAAG1 polypeptide corresponds to Genbank accession no. AAF23613, version no. AAF23613.1. In one embodiment, the nucleic acid encoding KAAG1 polypeptide corresponds to Genbank accession no. AF181722, version no AF181722.1. In some embodiments, the KAAG1 polypeptide has the sequence of SEQ ID NO.12.
PARP inhibitors
Poly (adenosine diphosphate [ADP]) ribose polymerase (PARP) are a family of enzymes involved in a wide range of cellular functions including DNA transcription, DNA damage response, genomic stability maintenance, cell cycle regulation, and cell death. PARP-1 is the most abundant and best characterised protein of this group. In oncology, its integral role in the repair of single-strand DNA breaks (SSBs) via the base excision repair (BER) pathway has been a focus of high interest and several PARP-1 inhibitors (PARPi) have been developed (including but not limited to Olaparib, CEP-9722, talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib) and are tested clinically. In cancer therapeutics, PARPi work predominantly by preventing the repair of DNA damage, ultimately causing cell death.
PARP is composed of four domains of interest: a DNA-binding domain, a caspase-cleaved domain, an auto-modification domain, and a catalytic domain. The DNA-binding domain is composed of two zinc finger motifs. In the presence of damaged DNA (base pair-excised), the DNA-binding domain will bind the DNA and induce a conformational shift. It has been shown that this binding occurs independent of the other domains. This is integral in a programmed cell death model based on caspase cleavage inhibition of PARP. The automodification domain is responsible for releasing the protein from the DNA after catalysis. Also, it plays an integral role in cleavage-induced inactivation.
PARP is found in the cell nucleus. The main role is to detect and initiate an immediate cellular response to metabolic, chemical, or radiation-induced single-strand DNA breaks (SSB) by signalling the enzymatic machinery involved in the SSB repair. Once PARP detects a SSB, it binds to the DNA, undergoes a structural change, and begins the synthesis of a polymeric adenosine diphosphate ribose (poly (ADP-ribose) or PAR) chain, which acts as a signal for the other DNA-repairing enzymes. Target enzymes include DNA ligase III (Ligll I), DNA polymerase beta (poip), and scaffolding proteins such as X-ray crosscomplementing gene 1 (XRCC1). After repairing, the PAR chains are degraded via Poly(ADP-ribose) glycohydrolase (PARG).
NAD+ is required as substrate for generating ADP-ribose monomers. It has been thought that overactivation of PARP may deplete the stores of cellular NAD+ and induce a progressive ATP depletion and necrotic cell death, since glucose oxidation is inhibited. But more recently it was suggested that inhibition of hexokinase activity leads to defects in glycolysis, (see Andrabi, PNAS 2014). Note below that PARP is inactivated by caspase-3 cleavage during programmed cell death.
PARP enzymes are essential in a number of cellular functions, including expression of inflammatory genes: PARP1 is required for the induction of ICAM-1 gene expression by smooth muscle cells, in response to TNF.
PBDs are a class of naturally occurring anti-tumor antibiotics found in Streptomyces. PBD dimers exert their cytotoxic mode of action via cross-linking of two strands of DNA, which results in the blockade of replication and tumor cell death. Importantly, the cross-links formed by PBD dimers are relatively non-distorting of the DNA structure, making them hidden to DNA repair mechanisms, which are often impaired in human tumors as opposed to normal tissues.
Combining PBD-based ADCs with PARPi (including but not limited to Olaparib, CEP-9722, talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib) is advantageous because repair of the DNA damaged caused by the PBD dimers is blocked by the PARP inhibition hence resulting in accumulation of DNA damage leading to cancer cell death.
To show that treatment of solid tumor-derived cell lines with PBD-based ADCs and PARPi has an additive or synergistic anti-tumor effect, a panel of solid tumor-derived cell lines will be treated with a range of concentration of each ADC and a PARPi. After incubation, the in vitro cytotoxicity of the combinations (as determined by CellTiter-Glo® or MTS assays) will be measured. Cytotoxic synergy is calculated by transforming the cell viability data into fraction affected, and calculating the combination index using the CalcuSyn analysis program.
"PARP inhibitor" means any chemical compound or biological molecule reduces PARP activity.
To examine the extent of inhibition of, e.g., PARP activity, samples or assays comprising a given, e.g., protein, gene, cell, or organism, are treated with a potential activating or inhibiting agent and are compared to control samples treated with an inactive control molecule. Control samples are assigned a relative activity value of 100%. Inhibition is achieved when the activity value relative to the control is about 90% or less, typically 85% or less, more typically 80% or less, most typically 75% or less, generally 70% or less, more generally 65% or less, most generally 60% or less, typically 55% or less, usually 50% or less, more usually 45% or less, most usually 40% or less, preferably 35% or less, more preferably 30% or less, still more preferably 25% or less, and most preferably less than 20%.
Specific PARPi suitable for use in the present disclosure include: a) Olaparib i. CAS Number → 763113-22-0
(see http://www.cas.org/content/chemical-substances/faqs) ii. NCBI Pubchem reference -> 23725625
(see https://pubchem.ncbi.nlm.nih.gov/) iii. Unique Ingredient Identifier (UNI I) -> W0H1 JD9AR8
(see http://www.fda.gov/Forlndustry/DataStandards/SubstanceRegistrati onSystem-UniquelngredientldentifierUNII/default.htm)
Formula I, olaparib: 4-[(3-[(4-cyclopropylcarbonyl)piperazin-1-yl]carbonyl) -4- fluorophenyl]methyl(2H)phthalazin-1-one b) CEP-9722 i. CAS Number -» 916574-83-9
Formula II, CEP-9722: 11-methoxy-2-((4-methylpiperazin-1-yl)methyl)-4,5,6,7-tetrahydro- 1 H-cyclopenta[a]pyrrolo[3,4-c]carbazole-1 ,3(2H)-dione c) BMN-673/talazoparib i. CAS Number → 1207456-01-6
(see http://www.cas.org/content/chemical-substances/faqs) ii. Unique Ingredient Identifier (UNI I) 9QHX048FRV
Formula III, talazoparib: (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1 ,2,4- triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one d) Rucaparib i. CAS Number 283173-50-2
(see http://www.cas.org/content/chemical-substances/faqs) ii. NCBI Pubchem reference - 9931954
(see https://pubchem.ncbi.nlm.nih.gov/) iii. Unique Ingredient Identifier (UNI I) -» 8237F3U7EH
(see http://www.fda.gov/Forlndustry/DataStandards/SubstanceRegistrati onSystem-UniquelngredientldentifierUNII/default.htm)
Formula IV, Rucaparib: 8-Fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-
6H-azepino[5,4,3-cd]indol-6-one e) lniparib/SAR24-550/BSI-201 i. CAS Number 160003-66-7
(see http://www.cas.org/content/chemical-substances/faqs) ii. NCBI Pubchem reference - 9796068
(see https://pubchem.ncbi.nlm.nih.gov/) iii. Unique Ingredient Identifier (UNI I) 2ZWI7KHK8F
(see http://www.fda.gov/Forlndustry/DataStandards/SubstanceRegistrati onSystem-UniquelngredientldentifierUNII/default.htm)
Formula V, Iniparib: 4-lodo-3-nitrobenzamide f) Veliparib (ABT-888) i. CAS Number -» 912444-00-9
(see http://www.cas.org/content/chemical-substances/faqs) ii. NCBI Pubchem reference -> 11960529
Formula VI, Veliparib: 2-((R)-2-Methylpyrrolidin-2-yl)-1 H-benzimidazole-4-carboxamide g) Niraparib/MK-4827 i. CAS Number 1038915-60-4
(see http://www.cas.org/content/chemical-substances/faqs) ii. NCBI Pubchem reference -> 24958200
(see https://pubchem.ncbi.nlm.nih.gov/) iii. Unique Ingredient Identifier (UNI I) HMC2H89N35
(see http://www.fda.gov/Forlndustry/DataStandards/SubstanceRegistrati onSystem-UniquelngredientldentifierUNII/default.htm)
3-aminobenzamide i. CAS Number -» 3544-24-9
(see http://www.cas.org/content/chemical-substances/faqs) ii. NCBI Pubchem reference -> 1645
Formula VIII: 3-Aminobenzamide j) E7016 i. CAS Number 902128-92-1
Formula IX, E7016: Benzopyrano(4,3,2-de)phthalazin-3(2H)-one, 10-((4-hydroxy-1- piperidinyl)methyl)-
In some embodiments, PARP polypeptide is PARP1 , which corresponds to Genbank accession no. AAA60137, version no. AAA60137.1 , record update date: Jun 23, 2010 08:48 AM. In one embodiment, the nucleic acid encoding PARP1 polypeptide corresponds to Genbank accession no. M18112, version no. M18112.1 , record update date: Jun 23, 2010 08:48 AM. In some embodiments, PARP1 polypeptide corresponds to Uniprot/Swiss- Prot accession No. P09874.
Advantageous properties of the described combinations
Both the anti-KAAG1 ADC and PARP inhibitor when used as a single agent in isolation have demonstrated clinical utility - for example, in the treatment of cancer. However, as described herein, combination of the anti-KAAG1 ADC and PARP inhibitor is expected to provide one or more of the following advantages over treatment with either anti-KAAG1 ADC or PARP inhibitor alone:
1) effective treatment of a broader range of cancers;
2) effective treatment of resistant or refractory forms of disorders such as cancer, and individuals with disorders such as cancer who have relapsed after a period of remission;
3) increased response rate to treatment; and / or
4) Increased durability of treatment.
Effective treatment of a broader range of cancers as used herein means that following treatment with the combination a complete response is observed with a greater range of recognised cancer types. That is, a complete response is seen from cancer types not previously reported to completely respond to either anti-KAAG1 ADC or PARP inhibitor alone.
Effective treatment of a resistant, refractory, or relapsed forms as used herein means that following treatment with the combination a complete response is observed in individuals that are either partially or completely resistant or refractory to treatment with either anti-KAAG1 ADC or PARP inhibitor alone (for example, individuals who show no response or only partial response following treatment with either agent alone, or those with relapsed disorder). In some embodiments, a complete response following treatment with the anti-KAAG1 ADC I PARP inhibitor combination is observed at least 10% of individuals that are either partially or completely resistant or refractory to treatment with either anti-KAAG1 ADC or PARP inhibitor alone. In some embodiments, a complete response following treatment with the anti-KAAG1 ADC / PARP inhibitor combination is observed at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% of individuals that are either partially or completely resistant or refractory to treatment with either anti-KAAG1 ADC or PARP inhibitor alone.
Increased response rate to treatment as used herein means that following treatment with the combination a complete response is observed in a greater proportion of individuals than is observed following treatment with either anti-KAAG1 ADC or PARP inhibitor alone. In some embodiments, a complete response following treatment with the anti-KAAG1 ADC / PARP inhibitor combination is observed at least 10% of treated individuals. In some embodiments, a complete response following treatment with the anti-KAAG1 ADC / PARP inhibitor combination is observed at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% of treated individuals.
Increased durability of treatment as used herein means that average duration of complete response in individuals treated with the combination is longer than in individuals who achieve complete response following treatment with either anti-KAAG1 ADC or PARP inhibitor alone. In some embodiments, the average duration of a complete response following treatment with the anti-KAAG1 ADC / PARP inhibitor combination is at least 6 months. In some embodiments, the average duration of a complete response following treatment with the anti-KAAG1 ADC / PARP inhibitor combination is at least 12 months, at least 18 months, at least 24 months, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, at least 10 years, at least 15 years, or at least 20 years.
‘Complete response’ is used herein to mean the absence of any clinical evidence of disease in an individual. Evidence may be assessed using the appropriate methodology in the art, for example CT or PET scanning, or biopsy where appropriate. The number of doses required to achieve complete response may be one, two, three, four, five, ten or more. In some embodiments the individuals achieve complete response no more than a year after administration of the first dose, such as no more than 6 months, no more than 3 months, no more than a month, no more than a fortnight, or no more than a week after administration of the first dose.
Treated disorders
The combined therapies described herein include those with utility for anticancer activity. In particular, in certain aspects the therapies include an antibody conjugated, i.e. covalently attached by a linker, to a PBD drug moiety, i.e. toxin. When the drug is not conjugated to an antibody, the PBD drug has a cytotoxic effect. The biological activity of the PBD drug moiety is thus modulated by conjugation to an antibody. The antibody-drug conjugates (ADC) of the disclosure selectively deliver an effective dose of a cytotoxic agent to tumor tissue whereby greater selectivity, i.e. a lower efficacious dose, may be achieved.
Thus, in one aspect, the present disclosure provides combined therapies comprising administering an anti-KAAG1 ADC which binds KAAG1 for use in therapy, wherein the method comprises selecting a subject based on expression of the target protein.
In one aspect, the present disclosure provides a combined therapy with a label that specifies that the therapy is suitable for use with a subject determined to be suitable for such use. The label may specify that the therapy is suitable for use in a subject has expression of KAAG1 , such as overexpression of KAAG1. The label may specify that the subject has a particular type of cancer.
In a further aspect there is also provided a combined therapy as described herein for use in the treatment of a proliferative disease. Another aspect of the present disclosure provides the use of a conjugate compound in the manufacture of a medicament for treating a proliferative disease.
One of ordinary skill in the art is readily able to determine whether or not a candidate combined therapy treats a proliferative condition for any particular cell type. For example, assays which may conveniently be used to assess the activity offered by a particular compound are described below.
The combined therapies described herein may be used to treat a proliferative disease. The term “proliferative disease” pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo.
Examples of proliferative conditions include, but are not limited to, benign, pre malignant, and malignant cellular proliferation, including but not limited to, neoplasms and tumours (e.g. histocytoma, glioma, astrocyoma, osteoma), cancers (e.g. lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma), lymphomas, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g. of connective tissues), and atherosclerosis.
Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g. bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.
Disorders of particular interest include, but are not limited to cancers, including metastatic cancers and metastatic cancer cells, such as circulating tumour cells, which may be found circulating in body fluids such as blood or lymph.
Cancers of particular interest include ovarian, breast, prostate, and renal cancer, cholangiacarcinoma, and sarcoma.
Other disorders of interest include any condition in which KAAG1 is overexpressed, or wherein KAAG1 antagonism will provide a clinical benefit. The proliferative disease may be characterised by the presence of a neoplasm comprising both KAAG1+ve and KAAG1-ve cells.
The proliferative disease may be characterised by the presence of a neoplasm composed of KAAG1-ve neoplastic cells, optionally wherein the KAAG1-ve neoplastic cells are associated with KAAG1+ve non-neoplastic cells.
The target neoplasm or neoplastic cells may be all or part of a solid tumour.
Solid tumors may be neoplasms comprising or composed of KAAG1+ve neoplastic cells. Solid tumors may be neoplasms infiltrated with KAAG1+ve cells; such solid tumours may lack expression of KAAG1 (that is, comprise or be composed of KAAG1-ve neoplastic cells).
Generally, the disease or disorder to be treated is a hyperproliferative disease such as cancer. Examples of cancer to be treated herein include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g. epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
In some aspects, the subject has a proliferative disorder selected from lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma,
In some aspects, the subject has a proliferative disease characterised by the presence of a neoplasm comprising both KAAG1+ve and KAAG1-ve cells.
The proliferative disease may be characterised by the presence of a neoplasm composed of KAAG1-ve neoplastic cells, optionally wherein the KAAG1-ve neoplastic cells are associated with KAAG1+ve non-neoplastic cells.
The target neoplasm or neoplastic cells may be all or part of a solid tumour.
BRCA-associated cancers
Mutations in either BRCA1 or BRCA2 strongly predispose individuals to a range of cancers, notably of the breast, ovaries, pancreas and prostate gland. Tumours arising in individuals carrying a single mutant BRCA allele exhibit loss of heterozygosity at the BRCA locus, losing the wild-type allele and retaining the mutant copy of the gene, suggesting that BRCA1 and BRCA2 act as tumour suppressors (Tutt AN, et al.. Cold Spring Harb Symp Quant Biol 2005; 70:139-48.). BRCA1 or BRCA2 deficient cells have defects in the repair of DNA double-strand breaks (DSBs) by the conservative, error-free pathway of homologous recombination (HR), leading to cellular sensitivity to specific DNA damaging agents (Tutt et al., ibid.). This mechanism has been exploited in the development of therapies to treat BRCA-associated cancers, including the demonstration that inhibition of the DNA repair enzyme Poly(ADP)-ribose Polymerase (PARP) is particularly selective for BRCA deficient cells (Farmer H, et al., Nature 2005; 434:917-21 ; Bryant HE, et al., Nature 2005; 434:913-7.).
The efficacy of the PARP inhibitor (PARPi) comprising combination therapies described herein is demonstrated in Example 1 , which shows synergistic in vivo therapeutic activity of the combination therapy in a BRCA1 mutant background. Example 3 further describes synergistic and additive in vitro therapeutic activity of the combination therapy in a wild type BRCA1 and BRCA2 background.
Accordingly, in some aspects the disorder treated by the combination therapies disclosed herein is a BRCA-associated cancer. In other aspects the disorder treated by the combination therapies disclosed herein is a cancer that is not BRCA-associated.
In some aspects the BRCA-associated cancer has a mutation in a BRCA1 and/or BRCA2 gene. The mutation may be a spontaneous mutation or inherited mutation.
In some aspects the BRCA-associated cancer is characterised by cancer cells having a mutation in a BRCA1 and/or BRCA2 gene.
The presence of a mutation in a BRCA gene may be determined by, for example, using direct sequencing, hybridisation to a probe, restriction fragment length polymorphism (RFLP) analysis, single-stranded conformation polymorphism (SSCP), PCR amplification of specific alleles, amplification of DNA target by PCR followed by a mini-sequencing assay, allelic discrimination during PCR, Genetic Bit Analysis, pyrosequencing, oligonucleotide ligation assay, analysis of melting curves or testing for a loss of heterozygosity (LOH).
In some aspects the BRCA-associated cancer is characterised by cancer cells exhibiting epigenetic inactivation of BRCA1 and/or BRCA2, for example by promoter hypermethylation. The epigenetic inactivation may be determined by, for example, methylation specific PCR to detect silencing of BRCA genes.
In some aspects, the BRCA-associated cancer is characterised by cancer cells exhibiting loss of BRCA1 or BRCA2 function
The BRCA-associated cancer may be characterised by defects or inactivation of BRCA1 and/or BRCA2 genes that are associated with the individual’s cancerous and non- cancerous cells. For example, if the individual had a germline mutation in BRCA1 and/or BRCA2. Alternatively or additionally, the BRCA-associated cancer may be characterised by defects or inactivation of BRCA1 and/or BRCA2 genes that are associated with the individual’s cancerous cells as opposed to the individual's non-cancerous cells, and in particular individuals whose tumours exhibit a defect in homologous recombination, the DNA repair mechanism controlled by BRCA1 and BRCA2.
Examples of BRCA-associated cancer include female and male breast cancer, ovarian cancer, pancreatic cancer and prostate cancer (see, for example, J Mersch et al., Cancer. 2015 Jan 15; 121(2): 269-275.)
Patient Selection
In certain aspects, the individuals are selected as suitable for treatment with the combined treatments before the treatments are administered.
As used herein, individuals who are considered suitable for treatment are those individuals who are expected to benefit from, or respond to, the treatment. Individuals may have, or be suspected of having, or be at risk of having cancer. Individuals may have received a diagnosis of cancer. In particular, individuals may have, or be suspected of having, or be at risk of having, ovarian, breast, prostate or renal cancer. In some cases, individuals may have, or be suspected of having, or be at risk of having, a solid cancer that has tumour associated non-tumor cells that express KAAG1 , such as infiltrating cells that express KAAG1.
In some aspects, subjects are selected on the basis of the amount or pattern of expression of KAAG1. In some aspects, the selection is based on expression of KAAG1 at the cell surface in a tissue or structure of interest. So, in some cases, subjects are selected on the basis they have, or are suspected of having, are at risk of having, or have received a diagnosis of a proliferative disease characterized by the presence of a neoplasm comprising or associated with cells having surface expression of KAAG1. The neoplasm may be composed of cells having surface expression of KAAG1.
In some aspects, subjects are selected on the basis they have a neoplasm comprising both KAAG1+ve and KAAG1-ve cells. The neoplasm may be composed of KAAG1-ve neoplastic cells, optionally wherein the KAAG1-ve neoplastic cells are associated with KAAG1+ve non-neoplastic cells. The neoplasm or neoplastic cells may be all or part of a solid tumour. The solid tumour may be partially or wholly KAAG1-ve, and may be infiltrated with KAAG1+ve cells.
In some cases, expression of KAAG1 in a particular tissue of interest is determined. For example, in a sample of tumor tissue. In some cases, systemic expression of KAAG1 is determined. For example, in a sample of circulating fluid such as blood, plasma, serum or lymph.
In some aspects, the subject is selected as suitable for treatment due to the presence of KAAG1 expression in a sample. In those cases, subjects without KAAG1 expression may be considered not suitable for treatment.
In other aspects, the level of KAAG1 expression is used to select a subject as suitable for treatment. Where the level of expression of the target is above a threshold level, the subject is determined to be suitable for treatment.
In some aspects, an subject is indicated as suitable for treatment if cells obtained from the tumour react with antibodies against KAAG1 as determined by IHC.
In some aspects, a subject is determined to be suitable for treatment if at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more of all cells in the sample express KAAG1. In some aspects disclosed herein, a subject is determined to be suitable for treatment if at least at least 5% of the cells in the sample express KAAG1.
In certain aspects, the target is PARP. In some aspects, the selection is based on expression of PARP.
In some aspects, the selection is based on levels of both KAAG1 at the cell surface and PARP.
In some aspects, the presence of KAAG1 and/or in cells in the sample indicates that the individual is suitable for treatment with a combination comprising an anti-KAAG1 ADC and a PARP inhibitor. In other aspects, the amount of KAAG1 and/or expression must be above a threshold level to indicate that the individual is suitable for treatment. In some aspects, the observation that KAAG1 and/or localisation is altered in the sample as compared to a control indicates that the individual is suitable for treatment.
In some aspects, an individual is indicated as suitable for treatment if cells obtained from lymph node or extra nodal sites react with antibodies against KAAG1 and/or as determined by IHC.
In some aspects, a patient is determined to be suitable for treatment if at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more of all cells in the sample express KAAG1. In some aspects disclosed herein, a patient is determined to be suitable for treatment if at least at least 10% of the cells in the sample express KAAG1.
In some aspects, a patient is determined to be suitable for treatment if at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more of all cells in the sample express. In some aspects disclosed herein, a patient is determined to be suitable for treatment if at least at least 10% of the cells in the sample express.
In some aspects, the individual is selected as suitable for treatment based on their current or previous treatment regime. In some embodiments the individual is selected for treatment with the anti-KAAG1 ADC if the individual has been treated with a PARP inhibitor. In some embodiments the individual is selected for treatment with the anti-KAAG1 ADC if the individual is being treated with a PARP inhibitor. In some cases the individual is selected for treatment if they are refractory to treatment (or further treatment) with the PARP inhibitor. In some cases the PARP inhibitor may be Olaparib. In embodiments where the individual is undergoing, or has undergone, treatment with a PARP inhibitor, the anti-KAAG1 ADC may be administered in combination with a PARP inhibitor, or without continued administration of the PARP inhibitor.
In some embodiments the anti-KAAG1 ADC is administered to the selected individual in combination with a PARP inhibitor. In some embodiments the anti-KAAG1 ADC is administered to the selected individual without continued administration of a PARP inhibitor. The PARP inhibitor is preferably Olaparib.
The term ‘refractory to treatment (or further treatment) with the PARP inhibitor’ is used herein to mean that the disorder (such as cancer) does not respond, or has ceased to respond, to administration of the PARP inhibitor when administered as a monotherapy.
BRCA status
In some aspects the individual is selected for as suitable for treatment with the combination therapies disclosed herein based on their BRCA status.
In some embodiments the individual is selected for treatment if they have a mutation in a BRCA1 and/or BRCA2 gene. In some embodiments the individual is selected for treatment if they have BRCA-associated cancer as described herein.
In some embodiments the individual is selected for treatment if they do not have a mutation in a BRCA1 and/or BRCA2 gene. In some embodiments the individual is selected for treatment if they do not have a mutation in either of a BRCA1 and/or BRCA2 gene. In some embodiments the individual is selected for treatment if they have a cancer that is not a BRCA-associated cancer as described herein.
Samples
The sample may comprise or may be derived from: a quantity of blood; a quantity of serum derived from the individual’s blood which may comprise the fluid portion of the blood obtained after removal of the fibrin clot and blood cells; a quantity of pancreatic juice; a tissue sample or biopsy; or cells isolated from said individual.
A sample may be taken from any tissue or bodily fluid. In certain aspects, the sample may include or may be derived from a tissue sample, biopsy, resection or isolated cells from said individual.
In certain aspects, the sample is a tissue sample. The sample may be a sample of tumor tissue, such as cancerous tumor tissue. The sample may have been obtained by a tumor biopsy. In some aspects, the sample is a lymphoid tissue sample, such as a lymphoid lesion sample or lymph node biopsy. In some cases, the sample is a skin biopsy.
In some aspects the sample is taken from a bodily fluid, more preferably one that circulates through the body. Accordingly, the sample may be a blood sample or lymph sample. In some cases, the sample is a urine sample or a saliva sample.
In some cases, the sample is a blood sample or blood-derived sample. The blood derived sample may be a selected fraction of a individual’s blood, e.g. a selected cell-containing fraction or a plasma or serum fraction.
A selected cell-containing fraction may contain cell types of interest which may include white blood cells (WBC), particularly peripheral blood mononuclear cells (PBC) and/or granulocytes, and/or red blood cells (RBC). Accordingly, methods according to the present disclosure may involve detection of a first target polypeptide or nucleic acid in the blood, in white blood cells, peripheral blood mononuclear cells, granulocytes and/or red blood cells.
The sample may be fresh or archival. For example, archival tissue may be from the first diagnosis of an individual, or a biopsy at a relapse. In certain aspects, the sample is a fresh biopsy.
The first target polypeptide may be KAAG1.
Individual status
The individual may be an animal, mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a monotreme (e.g., duckbilled platypus), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human.
Furthermore, the individual may be any of its forms of development, for example, a foetus. In one preferred embodiment, the individual is a human. The terms “subject”, “patient” and “individual” are used interchangeably herein.
In some aspects disclosed herein, an individual has, or is suspected as having, or has been identified as being at risk of, cancer. In some aspects disclosed herein, the individual has already received a diagnosis of cancer. The individual may have received a diagnosis of a proliferative disease characterised by the presence of a neoplasm comprising both KAAG1+ve and KAAG1-ve cells.
The proliferative disease may be characterised by the presence of a neoplasm composed of KAAG1-ve neoplastic cells, optionally wherein the KAAG1-ve neoplastic cells are associated with KAAG1+ve non-neoplastic cells.
In some cases, the individual has received a diagnosis of a solid tumour containing KAAG1+ expressing infiltrating cells.
Solid tumors may be neoplasms, including non-haematological cancers, comprising or composed of KAAG1+ve neoplastic cells. Solid tumors may be neoplasms, including non-
haematological cancers, infiltrated with KAAG1+ve cells; such solid tumours may lack expression of KAAG1 (that is, comprise or be composed of KAAG1-ve neoplastic cells).
The Individual may be undergoing, or have undergone, a therapeutic treatment for that cancer. The subject may, or may not, have previously received ADCT-901 . In some cases the cancer is ovarian, breast, prostate or renal cancer.
The Individual may be undergoing, or have undergone, treatment with a PARP inhibitor. In some cases the individual may be refractory to treatment (or further treatment) with the PARP inhibitor. In some cases the PARP inhibitor may be Olaparib. In embodiments where the individual is undergoing, or has undergone, treatment with a PARP inhibitor, the anti-KAAG1 ADC may be administered in combination with a PARP inhibitor, or without continued administration of the PARP inhibitor.
Controls
In some aspects, target expression in the individual is compared to target expression in a control. Controls are useful to support the validity of staining, and to identify experimental artefacts.
In some cases, the control may be a reference sample or reference dataset. The reference may be a sample that has been previously obtained from an individual with a known degree of suitability. The reference may be a dataset obtained from analyzing a reference sample.
Controls may be positive controls in which the target molecule is known to be present, or expressed at high level, or negative controls in which the target molecule is known to be absent or expressed at low level.
Controls may be samples of tissue that are from individuals who are known to benefit from the treatment. The tissue may be of the same type as the sample being tested. For example, a sample of tumor tissue from an individual may be compared to a control sample of tumor tissue from an individual who is known to be suitable for the treatment, such as an individual who has previously responded to the treatment.
In some cases the control may be a sample obtained from the same individual as the test sample, but from a tissue known to be healthy. Thus, a sample of cancerous tissue from an individual may be compared to a non-cancerous tissue sample.
In some cases, the control is a cell culture sample.
In some cases, a test sample is analyzed prior to incubation with an antibody to determine the level of background staining inherent to that sample.
In some cases an isotype control is used. Isotype controls use an antibody of the same class as the target specific antibody, but are not immunoreactive with the sample. Such
controls are useful for distinguishing non-specific interactions of the target specific antibody.
The methods may include hematopathologist interpretation of morphology and immunohistochemistry, to ensure accurate interpretation of test results. The method may involve confirmation that the pattern of expression correlates with the expected pattern. For example, where the amount of KAAG1 and/or PARP expression is analyzed, the method may involve confirmation that in the test sample the expression is observed as membrane staining, with a cytoplasmic component. The method may involve confirmation that the ratio of target signal to noise is above a threshold level, thereby allowing clear discrimination between specific and non-specific background signals.
Methods of Treatment
The term “treatment,” as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, regression of the condition, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e., prophylaxis, prevention) is also included.
The term “therapeutically-effective amount” or “effective amount” as used herein, pertains to that amount of an active compound, or a material, composition or dosage from comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
Similarly, the term “prophylactically-effective amount,” as used herein, pertains to that amount of an active compound, or a material, composition or dosage from comprising an active compound, which is effective for producing some desired prophylactic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
Disclosed herein are methods of therapy. Also provided is a method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of an anti-KAAG1 ADC and a PARP inhibitor. The term “therapeutically effective amount” is an amount sufficient to show benefit to a subject. Such benefit may be at least amelioration of at least one symptom. The actual amount administered, and rate and timecourse of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage, is within the responsibility of general practitioners and other medical doctors. The subject may have been tested to determine their eligibility to receive the treatment according to the methods disclosed herein. The method of treatment may comprise a step of determining whether a subject is eligible for treatment, using a method disclosed herein.
The anti-KAAG1 ADC comprises an anti-KAAG1 antibody. The anti-KAAG1 antibody may be 3A4 as disclosed herein. The ADC may comprise a drug which is a PBD dimer. The ADC may be an anti-KAAG1-ADC such as ADCT-901. The ADC may be an ADC disclosed in PCT/EP2020/065506.
The PARP inhibitor may be Olaparib (ABT-199), CEP-9722, BMN-673/talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib, 3-Aminobenzamide, or E7016. Preferably the PARP inhibitor is Olaparib (ABT-199).
The treatment may involve administration of the anti-KAAG1 ADC / PARP inhibitor combination alone or in further combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.
An example method of treatment involves:
(1) identifying an individual has been treated with, or is being treated with a PARP inhibitor, such as Olaparib;
(2) administering to the individual an anti-KAAG1 ADC, such as ADCT-901 ; and, optionally
(3) administering to the individual a PARP inhibitor, such as Olaparib in combination with the anti-KAAG1 ADC (for example, at the same time as the ADC, or after the ADC).
Examples of treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g. drugs, such as chemotherapeutics); surgery; and radiation therapy.
A “chemotherapeutic agent” is a chemical compound useful in the treatment of cancer, regardless of mechanism of action. Classes of chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, spindle poison plant alkaloids, cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors. Chemotherapeutic agents include compounds used in “targeted therapy” and conventional chemotherapy.
Examples of chemotherapeutic agents include: Lenalidomide (REVLIMID®, Celgene), Vorinostat (ZOLINZA®, Merck), Panobinostat (FARYDAK®, Novartis), Mocetinostat (MGCD0103), Everolimus (ZORTRESS®, CERTICAN®, Novartis), Bendamustine (TREAKISYM®, RIBOMUSTIN®, LEVACT®, TREANDA®, Mundipharma International), erlotinib (TARCEVA®, Genentech/OSI Pharm.), docetaxel (TAXOTERE®, Sanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS No. 51-21-8), gemcitabine (GEMZAR®, Lilly), PD- 0325901 (CAS No. 391210-10-9, Pfizer), cisplatin (cis-diamine, dichloroplatinum(ll), CAS No. 15663-27-1), carboplatin (CAS No. 41575-94-4), paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.J.), trastuzumab (HERCEPTIN®, Genentech), temozolomide (4-methyl-5-oxo- 2,3,4,6,8-pentazabicyclo [4.3.0] nona-2,7,9-triene- 9- carboxamide, CAS No. 85622-93-1 , TEMODAR®, TEMODAL®, Schering Plough), tamoxifen ((Z)-2-[4-(1 ,2-diphenylbut-1-enyl)phenoxy]-A/,/V-dimethylethanamine,
NOLVADEX®, ISTUBAL®, VALODEX®), and doxorubicin (ADRIAMYCIN®), Akti-1/2, HPPD, and rapamycin.
More examples of chemotherapeutic agents include: oxaliplatin (ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent (SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), XL-518 (Mek inhibitor, Exelixis, WO 2007/044515), ARRY-886 (Mek inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK 222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin (folinic acid), rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), lonafarnib (SARASAR™, SCH 66336, Schering Plough), sorafenib (NEXAVAR®, BAY43-9006, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), irinotecan (CAMPTOSAR®, CPT-11 , Pfizer), tipifarnib (ZARNESTRA™, Johnson & Johnson), ABRAXANE™ (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, II), vandetanib (rINN, ZD6474, ZACTIMA®, AstraZeneca), chloranmbucil, AG1478, AG1571 (SU 5271 ; Sugen), temsirolimus (TORISEL®, Wyeth), pazopanib (GlaxoSmithKline), canfosfamide (TELCYTA®, Telik), thiotepa and cyclosphosphamide (CYTOXAN®, NEOSAR®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g. calicheamicin, calicheamicin gammal I, calicheamicin omegall (Angew Chem. Inti. Ed. Engl. (1994) 33:183-186); dynemicin, dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzi nostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, nemorubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine,
azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2”-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®, Roche); ibandronate; CPT-11 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above. Combinations of agents may be used, such as CHP (doxorubicin, prednisone, cyclophosphamide), or CHOP (doxorubicin, prednisone, cyclophopsphamide, vincristine).
Also included in the definition of “chemotherapeutic agent” are: (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a 1 ,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors such as MEK inhibitors (WO 2007/044515); (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, for example, PKC- alpha, Raf and H-Ras, such as oblimersen (GENASENSE®, Genta Inc.); (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN® rlL-2; topoisomerase 1 inhibitors such as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such as bevacizumab (AVAST! N®, Genentech); and pharmaceutically acceptable salts, acids and derivatives of any of the above.
Also included in the definition of “chemotherapeutic agent” are therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), pertuzumab (PERJETA™, OMNITARG™, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), MDX-060 (Medarex) and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).
Humanized monoclonal antibodies with therapeutic potential as chemotherapeutic agents in combination with the conjugates of the disclosure include: alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, and visilizumab.
Compositions according to the present disclosure are preferably pharmaceutical compositions. Pharmaceutical compositions according to the present disclosure, and for use in accordance with the present disclosure, may comprise, in addition to the active ingredient, i.e. a conjugate compound, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g. cutaneous, subcutaneous, or intravenous.
Pharmaceutical compositions for oral administration may be in tablet, capsule, powder or liquid form. A tablet may comprise a solid carrier or an adjuvant. Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included. A capsule may comprise a solid carrier such a gelatin.
For intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection. Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required.
Dosage
It will be appreciated by one of skill in the art that appropriate dosages of the anti-KAAG1 ADC and/or the PARP inhibitor, and compositions comprising these active elements, can vary from subject to subject. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the subject. The amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
In certain aspects, the dosage of anti-KAAG1 ADC is determined by the expression of KAAG1 observed in a sample obtained from the subject. Thus, the level or localisation of expression of KAAG1 in the sample may be indicative that a higher or lower dose of anti-KAAG1 ADC is required. For example, a high expression level of KAAG1 may indicate that a higher dose of anti-KAAG1 ADC would be suitable. In some cases, a high expression level of KAAG1 may indicate the need for administration of another agent in addition to the anti-KAAG1 ADC. For example, administration of the anti-KAAG1 ADC in conjunction with a chemotherapeutic agent. A high expression level of KAAG1 may indicate a more aggressive therapy.
In certain aspects, the dosage of the PARP inhibitor is determined by the expression of observed in a sample obtained from the subject. Thus, the level or localisation of expression of in the sample may be indicative that a higher or lower dose of PARP inhibitor is required. For example, a high expression level of PARP may indicate that a higher dose of PARP inhibitor would be suitable. In some cases, a high expression level of PARP may indicate the need for administration of another agent in addition to the PARP inhibitor. For example, administration of the PARP inhibitor in conjunction with a chemotherapeutic agent. A high expression level of PARP may indicate a more aggressive therapy.
Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
In general, a suitable dose of each active compound is in the range of about 100 ng to about 25 mg (more typically about 1 pg to about 10 mg) per kilogram body weight of the subject per day. Where the active compound is a salt, an ester, an amide, a prodrug, or
the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
In one embodiment, each active compound is administered to a human subject according to the following dosage regime: about 100 mg, 3 times daily.
In one embodiment, each active compound is administered to a human subject according to the following dosage regime: about 150 mg, 2 times daily.
In one embodiment, each active compound is administered to a human subject according to the following dosage regime: about 200 mg, 2 times daily.
However in one embodiment, each conjugate compound is administered to a human subject according to the following dosage regime: about 50 or about 75 mg, 3 or 4 times daily.
In one embodiment, each conjugate compound is administered to a human subject according to the following dosage regime: about 100 or about 125 mg, 2 times daily.
For the anti-KAAG1 ADC, where it is a PBD bearing ADC, the dosage amounts described above may apply to the conjugate (including the PBD moiety and the linker to the antibody) or to the effective amount of PBD compound provided, for example the amount of compound that is releasable after cleavage of the linker.
The anti-KAAG1 ADC comprises an anti-KAAG1 antibody. The anti-KAAG1 antibody may be 3A4 as disclosed herein. The ADC may comprise a drug which is a PBD dimer. The ADC may be an anti-CDKAAG1-ADC such as ADCT-901. The ADC may be an ADC disclosed in PCT/EP2020/065506.
The PARP inhibitor may be Olaparib (ABT-199), CEP-9722, BMN-673/talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib, 3-Aminobenzamide, or E7016. Preferably the PARP inhibitor is Olaparib (ABT-199).
Antibodies
The term “antibody” herein is used in the broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies), intact antibodies (also described as “full-length” antibodies) and antibody fragments, so long as they exhibit the desired biological activity, for example, the ability to bind KAAG1 (Miller et al (2003) Jour, of Immunology 170:4854-4861). Antibodies may be murine, human, humanized, chimeric, or derived from other species such as rabbit, goat, sheep, horse or camel.
An antibody is a protein generated by the immune system that is capable of recognizing and binding to a specific antigen. (Janeway, C., Travers, P., Walport, M., Shlomchik (2001)
Immuno Biology, 5th Ed., Garland Publishing, New York). A target antigen generally has numerous binding sites, also called epitopes, recognized by Complementarity Determining Regions (CDRs) on multiple antibodies. Each antibody that specifically binds to a different epitope has a different structure. Thus, one antigen may have more than one corresponding antibody. An antibody may comprise a full-length immunoglobulin molecule or an immunologically active portion of a full-length immunoglobulin molecule, /.e., a molecule that contains an antigen binding site that immunospecifically binds an antigen of a target of interest or part thereof, such targets including but not limited to, cancer cell or cells that produce autoimmune antibodies associated with an autoimmune disease. The immunoglobulin can be of any type (e.g. IgG, IgE, IgM, IgD, and IgA), class (e.g. lgG1 , lgG2, lgG3, lgG4, lgA1 and lgA2) or subclass, or allotype (e.g. human G1m1 , G1m2, G1 m3, non-G1m1 [that, is any allotype other than G1m1], G1 m17, G2m23, G3m21 , G3m28, G3m11 , G3m5, G3m13, G3m14, G3m10, G3m15, G3m16, G3m6, G3m24, G3m26, G3m27, A2m1 , A2m2, Km1 , Km2 and Km3) of immunoglobulin molecule. The immunoglobulins can be derived from any species, including human, murine, or rabbit origin.
"Antibody fragments" comprise a portion of a full length antibody, generally the antigen binding or variable region thereof. Examples of antibody fragments include Fab, Fab', F(ab')2, and scFv fragments; diabodies; linear antibodies; fragments produced by a Fab expression library, anti-idiotypic (anti-ld) antibodies, CDR (complementary determining region), and epitope-binding fragments of any of the above which immunospecifically bind to cancer cell antigens, viral antigens or microbial antigens, single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.
The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e. the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations which include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, the monoclonal antibodies are advantageous in that they may be synthesized uncontaminated by other antibodies. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present disclosure may be made by the hybridoma method first described by Kohler eta! (1975) Nature 256:495, or may be made by recombinant DNA methods (see, US 4816567). The monoclonal antibodies may also be isolated from phage antibody libraries using the techniques described in Clackson et al (1991) Nature, 352:624- 628; Marks et al (1991) J. Mol. Biol., 222:581-597 or from transgenic mice carrying a fully human immunoglobulin system (Lonberg (2008) Curr. Opinion 20(4):450-459).
The monoclonal antibodies herein specifically include “chimeric” antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (US 4816567; and Morrison et al (1984) Proc. Natl. Acad. Sci. USA, 81 :6851-6855). Chimeric antibodies include “primatized” antibodies comprising variable domain antigen-binding sequences derived from a non-human primate (e.g. Old World Monkey or Ape) and human constant region sequences.
An “intact antibody” herein is one comprising VL and VH domains, as well as a light chain constant domain (CL) and heavy chain constant domains, CH1 , CH2 and CH3. The constant domains may be native sequence constant domains (e.g. human native sequence constant domains) or amino acid sequence variant thereof. The intact antibody may have one or more “effector functions” which refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody. Examples of antibody effector functions include C1q binding; complement dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; and down regulation of cell surface receptors such as B cell receptor and BCR.
Depending on the amino acid sequence of the constant domain of their heavy chains, intact antibodies can be assigned to different “classes.” There are five major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into “subclasses” (isotypes), e.g., lgG1 , lgG2, lgG3, lgG4, IgA, and lgA2. The heavy-chain constant domains that correspond to the different classes of antibodies are called a, 6, e, Y, and , respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
Brief Description of the Figures
Embodiments and experiments illustrating the principles of the disclosure will now be discussed with reference to the accompanying figures in which:
Figure 1. In vivo combination study of ADCT-901 and Olaparib in BRCA1 mut/BRCA2 wt, ovarian cancer PDX ; each line shows group mean ; ADCxKAAGI = ADCT-901
Figure 2. In vivo combination study of ADCT-901 and Olaparib in BRCA1 mut/BRCA2 wt, ovarian cancer PDX ; each line shows an individual animal ; ADCxKAAGI = ADCT-901
The disclosure includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided.
The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
Aspects and embodiments of the present disclosure will now be illustrated, by way of example, with reference to the accompanying figures. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.
Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise,” and variations such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment.
STATEMENTS OF INVENTION
1. A method of selecting an individual as suitable for treatment with an anti-KAAG1 ADC, wherein the individual is selected for treatment with the anti-KAAG1 ADC if the individual has been treated with a PARP inhibitor.
2. A method of selecting an individual as suitable for treatment with an anti-KAAG1 ADC, wherein the individual is selected for treatment with the anti-KAAG1 ADC if the individual is being treated with a PARP inhibitor.
3. The method according to any one of the preceding paragraphs, wherein the individual is selected for treatment if the individual is refractory to treatment, or further treatment, with the PARP inhibitor.
4. A method for treating a disorder in an individual, the method comprising:
(i) selecting an individual as suitable for treatment by a method according to any one of paragraphs 1 to 3; and
(ii) administering to the individual an effective amount of the anti-KAAG1 ADC.
5. The method according to paragraph 4, further comprising administering a PARP inhibitor in combination with the anti-KAAG1 ADC.
6. A method for treating a disorder in an individual, the method comprising administering to the individual an effective amount of an anti-KAAG1 ADC and PARP inhibitor.
7. The method according to paragraph 6, wherein the individual is selected for treatment according to a method according to any one of paragraphs 1 to 3.
8. The method according to any one of paragraphs 5 to 7, wherein the treatment comprises administering the anti-KAAG1 ADC before the PARP inhibitor, simultaneous with the PARP inhibitor, or after the PARP inhibitor.
9. The method according to any previous paragraph, wherein the treatment further comprises administering a chemotherapeutic agent.
10. The method according to any previous paragraph, wherein the individual is human.
11. The method according to any preceding paragraph, wherein the individual has a disorder or has been determined to have a disorder.
12. The method according to paragraph 11 , wherein the individual has, or has been has been determined to have, a cancer which expresses KAAG1 or KAAG1+ tumour- associated non-tumour cells, such as KAAG1+ infiltrating cells.
13. The method according to any previous paragraph, wherein the individual is undergoing treatment with a PARP inhibitor.
14. The method according to any previous paragraph, wherein the individual has undergone treatment with a PARP inhibitor.
15. The method according to any previous paragraph, wherein the individual is refractory to treatment, or further treatment, with the PARP inhibitor.
16. The method according to any one of the preceding paragraphs, wherein the treatment has increased efficacy as compared to monotherapy with either the anti-KAAG1 ADC or PARP inhibitor alone.
17. The method according to any preceding paragraph, wherein the anti-KAAG1 ADC is ADCT-901.
18. The method according to any previous paragraph, wherein the disorder is a proliferative disease.
19. The method according to paragraph 18, wherein the disorder is cancer.
20. The method according any previous paragraph, wherein the individual has, or has been has been determined to have, a disorder characterised by the presence of a neoplasm comprising both KAAG1+ve and KAAG1-ve cells.
21. The method according any previous paragraph, wherein the individual has, or has been has been determined to have, a disorder characterised by the presence of a neoplasm comprising, or composed of, KAAG1-ve neoplastic cells.
22. The method according to either of paragraphs 20 or 21 , wherein the neoplasm is all or part of a solid tumour.
23. The method of paragraphs 22, wherein the solid tumour is associated with KAAG1+ve infiltrating cells.
24. The method of any previous paragraph, wherein the disorder is selected from the group comprising: lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, and sarcoma.
25. The method of any previous paragraph, wherein the disorder is selected from the group comprising: ovarian, breast, prostate, renal cancer, cholangiacarcinoma, and sarcoma.
26. The method according to any one of paragraphs 19 to 25, wherein the cancer is a BRCA-associated cancer.
27. The method according to paragraph 26, wherein the BRCA-associated cancer has a mutation in a BRCA1 and/or BRCA2 gene.
28. The method according to paragraph 26, wherein the BRCA-associated cancer is characterised by cancer cells having a mutation in a BRCA1 and/or BRCA2.
29. The method according to any one of paragraphs 26 to 28, wherein the BRCA- associated cancer is characterised by cancer cells exhibiting loss of BRCA1 or BRCA2 function
30. The method according to any one of paragraphs 6 to 29, wherein the individual is selected for treatment if they have a mutation in a BRCA1 and/or BRCA2 gene.
31. The method according to any one of paragraphs 6 to 30, wherein the individual is selected for treatment if they have BRCA-associated cancer.
32. The method according to any one of paragraphs 19 to 25, wherein the cancer is not a BRCA-associated cancer.
33. The method according to any one of paragraphs 6 to 25 or 32, wherein the individual is selected for treatment if they have a cancer that is not a BRCA-associated cancer.
34. The method according to any previous paragraph, wherein the PARP inhibitor is selected from the group consisting of: Olaparib (ABT-199), CEP-9722, BMN- 673/talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib, 3-Aminobenzamide, or E7016.
35. The method according to any previous paragraph, wherein the PARP inhibitor is Olaparib.
36. The method according to any previous paragraph, wherein the PARP inhibitor is talazoparib.
37. The method according to any previous paragraph, wherein the anti-KAAG1 ADC is a conjugate of formula L - (DL)P, where DL is of formula I or II:
wherein: L is an antibody (Ab) that binds to KAAG1; when there is a double bond present between C2’ and C3’, R12 is selected from the group consisting of: (ia) C5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, carboxy, ester, C1-7 alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene; (ib) C1-5 saturated aliphatic alkyl; (ic) C3-6 saturated cycloalkyl;
wherein each of R21, R22 and R23 are independently selected from H, C1- 3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R12 group is no more than 5; R25b * 25a (ie) R , wherein one of R25a and R25b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and (if)
, where R 24 is selected from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; when there is a single bond present between C2’ and C3’, R12 is
, where R 26a and R 26b are independently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester; or, when one of R26a and R26b is H, the other is selected from nitrile and a C1-4 alkyl ester; R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR’, nitro, Me3Sn and halo; where R and R’ are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR’, nitro, Me3Sn and halo;
R″ is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, NRN2 (where RN2 is H or C1-4 alkyl), and/or aromatic rings, e.g. benzene or pyridine; Y and Y’ are selected from O, S, or NH; R6’, R7’, R9’ are selected from the same groups as R6, R7 and R9 respectively; [Formula I] RL1’ is a linker for connection to the antibody (Ab); R11a is selected from OH, ORA, where RA is C1-4 alkyl, and SOzM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; R20 and R21 either together form a double bond between the nitrogen and carbon atoms to which they are bound or; R20 is selected from H and RC, where RC is a capping group; R21 is selected from OH, ORA and SOzM; when there is a double bond present between C2 and C3, R2 is selected from the group consisting of: (ia) C5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, carboxy, ester, C1-7 alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene; (ib) C1-5 saturated aliphatic alkyl; (ic) C3-6 saturated cycloalkyl;
, wherein each of R11, R12 and R13 are independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R2 group is no more than 5; (ie)
, wherein one of R15a and R15b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and (if)
, where R14 is selected from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; when there is a single bond present between C2 and C3, R2 is , where R16a and R16b are independently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester; or, when one of R16a and R16b is H, the other is selected from nitrile and a C1-4 alkyl ester;
[Formula II] R22 is of formula IIIa, formula IIIb or formula IIIc:
where A is a C5-7 aryl group, and either (i) Q1 is a single bond, and Q2 is selected from a single bond and -Z-(CH2)n-, where Z is selected from a single bond, O, S and NH and n is from 1 to 3; or (ii) Q1 is -CH=CH-, and Q2 is a single bond;
where Q is selected from O-RL2’, S-RL2’ and NRN-RL2’, and RN is selected from H, methyl and ethyl X is selected from the group comprising: O-RL2’, S-RL2’, CO2-RL2’, CO-RL2’, NH-C(=O)-RL2’,
NHNH-RL2’, CONHNH-RL2’, , , NRNRL2’, wherein RN is selected from the group comprising H and C1-4 alkyl; RL2’ is a linker for connection to the antibody (Ab); R10 and R11 either together form a double bond between the nitrogen and carbon atoms to which they are bound or; R10 is H and R11 is selected from OH, ORA and SOzM; R30 and R31 either together form a double bond between the nitrogen and carbon atoms to which they are bound or; R30 is H and R31 is selected from OH, ORA and SOzM. 38. The method according to any previous paragraph, wherein the anti-KAAG1 ADC has the chemical structure:
.
wherein Ab is the antibody that binds KAAG1 .
39. The method according to any previous paragraph, wherein the anti-KAAG1 ADC comprises an antibody having a VH domain comprising a VH CDR1 , a VH CDR2, and a VH CDR3, wherein the antibody comprises the CDR sequences of the VH domain having the sequence according to SEQ ID NO: 1.
40. The method according to any previous paragraph, wherein the antibody comprises a VL domain comprising a VL CDR1 , a VL CDR2, and a VL CDR3, wherein the antibody comprises the CDR sequences of the VL domain having the sequence according to SEQ ID NO: 2.
41. The method according to any previous paragraph, wherein the anti-KAAG1 ADC comprises an antibody having a VH domain comprising a VH CDR1 with the amino acid sequence of SEQ ID NO.5, a VH CDR2 with the amino acid sequence of SEQ ID NO.6, and a VH CDR3 with the amino acid sequence of SEQ ID NO.7.
42. The method according to any previous paragraph, wherein the antibody comprises a VL domain comprising a VL CDR1 with the amino acid sequence of SEQ ID NO.8, a VL CDR2 with the amino acid sequence of SEQ ID NO.9, and a VL CDR3 with the amino acid sequence of SEQ ID NO.10.
43. The method according to any previous paragraph, wherein the anti-KAAG1 ADC comprises an antibody having a VH domain having the sequence according to SEQ ID NO:
1.
44. The method according to any previous paragraph, wherein the anti-KAAG1 ADC comprises an antibody having a VL domain having the sequence according to SEQ ID NO:
2.
45. The method according to any previous paragraph, wherein the anti-KAAG1 ADC is ADCT-901 .
46. The method according to any previous paragraph, wherein the anti-KAAG1 ADC is ADCT-901 and the PARP inhibitor is Olaparib.
47. The method according to any previous paragraph, wherein the anti-KAAG1 ADC is ADCT-901 and the PARP inhibitor is talazoparib.
48. An anti-KAAG1 ADC for use in a method of treatment according to any one of paragraphs 4 to 47.
49. A composition comprising an anti-KAAG1 ADC, for use in a method of treatment according to any one of paragraphs 4 to 47.
50. A PARP inhibitor for use in a method of treatment according to any one of paragraphs 5 to 47.
51. A composition comprising a PARP inhibitor, for use in a method of treatment according to any one of paragraphs 5 to 47.
52. Use of an anti-KAAG1 ADC in the manufacture of a medicament for treating a disorder in an individual, wherein the treatment comprises the method of any one of paragraphs 4 to 47.
53. Use of a PARP inhibitor in the manufacture of a medicament for treating a disorder in an individual, wherein the treatment comprises the method of any one of paragraphs 5 to 47.
54. A kit comprising: a first medicament comprising an anti-KAAG1 ADC; a package insert comprising instructions for administration of the first medicament according to the method of any one or paragraphs 4 to 47.
55. The kit according to paragraph 54, further comprising: A second medicament comprising a PARP inhibitor.
EXAMPLES
Example 1 : In vivo combination study of ADCT-901 and Olaparib in BRCA1 mut/BRCA2 wt, ovarian cancer PDX
Introduction
ADCT-901 (aka ADCxKAAGI) is an anti-KAAG1 antibody-drug conjugate (ADC) conjugated via a protease cleavable linker to SG3199, a highly cytotoxic DNA minor groove crosslinking pyrrolobenzodiazepine dimer (Flynn et al. Mol Cancer Ther 2016, and as described herein). The antibody employed 3A4 is a humanized version of the murine 3A4 antibody that was raised against human KAAG1 (see US9393392B2).
Methods
Female Athymic Nude-Foxn1 nu (Envigo) were at least 6-8 weeks old on Day 0 of the study and had a body weight (BW) range of 19.3 to 29.1 g.
BRCA-1-mutated, ovarian cancer PDX (CTG-0703) tumor fragments (approximately 5 x 5 x 5 mm3) were implanted subcutaneously in the left flank of the female pre-study mice. Each animal was implanted with a specific passage lot and documented (passage 6). T umor growth was monitored twice a week using digital calipers and the tumor volume (TV) was calculated using the formula (0.52 x [length x width2]). When the TV reached approximately 150-300 mm3, animals were matched by tumor size and randomized into vehicle control and treatment groups (n = 8/group). Dosing was initiated on Day 0. After the initiation of dosing, animals were weighed using a digital scale twice a week and TV was also measured twice per week.
ADCxKAAGI was administered intravenously as single dose at 0.5 mg/kg (0,5 mg/kg, qdx1) on day 0; olaparib was administered by oral gavage at 50 mg/kg every day for 28 days (50 mg/kg, qdx28) starting from day 0. In the combination setting, both drugs were administered concomitantly on day 0 and then the subsequent doses of Olaparib were administered as per its monotherapy schedule. The dosing volume was 0.2 mL per 20 grams of body weight (10 mL/kg), and was scaled to the body weight of each individual animal.
The study endpoint was when individual tumor volumes reached 1500 mm3 or Day 60, whichever occurred first.
Results
See also Figures 1 and 2.
Example 2: prophetic clinical trial
The purpose of this proposed study is to preliminarily assess the safety, tolerability, pharmacological and clinical activity of this combination
The following cancer types have been chosen for study: Disease A, Disease B, and Disease C
Evidence for efficacy as single agents exists for both drugs:
• anti KAAG1 ADC (see, for example, see, for example, PCT/EP2020/065506)
• PARP inhibitor (see KS Peggs et al., 2009, Clinical and Experimental Immunology, 157: 9-19 [doi: 10.1111/j.1365-2249.2009.03912.x])
This primary purpose of this study is to explore whether these agents can be safely combined, and if so, will identify the dose(s) and regimens appropriate for further study. The study will also assess whether each combination induces pharmacologic changes in tumor that would suggest potential clinical benefit.
In addition, it will provide preliminary evidence that a combination may increase the response rate and durability of response compared with published data for treatment with single agent anti-KAAG1 ADC or PARP inhibitor.
Each disease group may include a subset of patients previously treated with the PARP inhibitor to explore whether combination therapy might overcome resistance to PARP inhibitor therapy. For each disease, it is not intended to apply specific molecular selection as the data available at present generally do not support excluding patients on the basis of approved molecular diagnostic tests.
Rationale for anti KAAG1 ADC starting dose
The RDE for already established f o r ADC (in ug/kg administered every three weeks) will be used for all patients in this study. To ensure patient safety, a starting dose below the RDE will be used; the starting dose level will be one where patient benefit could still be demonstrated in study ADC1 , suggesting that patients enrolled at such dose level will gain at least some benefit by taking part.
Rationale for PARP inhibitor starting dose
The RDE for already established f o r the PARP inhibitor (in ug/kg administered every three weeks) will be used for all patients in this study. To ensure patient safety, a starting dose below the RDE will be used; the starting dose level will be one where patient benefit could still be demonstrated in study SA1 , suggesting that patients enrolled at such dose level will gain at least some benefit by taking part.
Study design
This phase lb, multi-center, open-label study to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of the ADC
in combination with the PARP inhibitor, in patients with disease A, disease B, and disease C.
The study is comprised of a dose escalation part followed by a dose expansion part.
Dose escalation will start with reduced starting doses (compared to their respective recommended phase 2 or licensed dose levels), for both ADC and the PARP inhibitor, to guarantee patient safety. Starting doses will be 33% (or 50%) of the RDE for each compound. Subsequently, doses will be first escalated for the PARP inhibitor until the RDE or licensed dose has been reached, or a lower dose if necessary for tolerability reasons. Then, the dose for ADC will be escalated, until the RDE for combination treatment is reached.
A perceived safe starting dose of 33% of the intended efficacious dose is proposed for both compounds, but this may need adaptation to lower or higher, as the individual risk profile for the combination may be.
Compound 1 should be the compound for which an efficatious clinical dose has been firmly established (at 100%), and which is therefore aimed to be reached quickly in the trial patients by first escalating the dose of this compound.
If the dose combination is determined to be safe, it may be tested in additional patients to confirm the safety and tolerability at that dose level. Further tailoring of the dose of each compound may be conducted, and/or the regimen may be modified.
The dose escalation of the combination will be guided by a Bayesian Logistic Regression Model (BLRM) based on any Dose Limiting Toxicities (DLTs) observed in the first (or first two, TBC) cycles of therapy. Use of a BLRM is a well-established method to estimate the maximum tolerated dose (MTD)/ recommended dose for expansion (RDE) in cancer patients. The adaptive BLRM will be guided by the Escalation With Overdose Control (EWOC) principle to control the risk of DLT in future patients on the study. The use of Bayesian response adaptive models for small datasets has been accepted by FDA and EMEA ("Guideline on clinical trials in small populations", February 1 , 2007) and endorsed by numerous publications (Babb et al. 1998, Neuenschwander et al. 2008).
The decisions on new dose combinations are made by the Investigators and sponsor study personnel in a dose escalation safety call (DESC) based upon the review of patient tolerability and safety information (including the BLRM summaries of DLT risk, if applicable) along with PK, PD and preliminary activity information available at the time of the decision.
Once the MTD(s)/RDE is determined for the combination, the expansion part of the study may be initiated to further assess the safety, tolerability and preliminary efficacy.
■ For combinations with IO, changes in the immune infiltrate in tumors will also be characterized following combination treatment in the target disease indications.
Given the available prior clinical experience with the agents in this study, it is expected that in most cases a combination dose can be identified without testing a large number of dose levels or schedules. To assess the pharmacodynamic activity of the combinations, patients will be asked to undergo a tumor biopsy at baseline and again after approximately two cycles of therapy.
■ For IO combo: The extent of the change in tumor infiltration by immune cells including lymphocytes and macrophages will contribute to a decision on any potential benefit.
Dose escalation part
During the dose escalation part of the study, patients will be treated with a fixed dose of ADC administered i.v. , and increasing doses of the PARP inhibitor until the RDE for the PARP inhibitor has been reached. Subsequently, doses of ADC are increased (in different cohorts) while the dose for the PARP inhibitor is kept constant.
Two to approximately 3 or 4 patients with disease A, disease B or disease C will be treated in each escalation cohort until the determination of MTD(s)/RDE(s) is determined.
There will be a 24-hour observation before enrolling the second patient at Dose Level 1. The DLT observation period at each dose level is either 1 cycle (3 weeks) or 2 cycles (6 weeks) as mandated by the appropriate authorities for IO therapies, after which it will be determined whether to escalate to the next dose level, stay at the current dose level, or de- escalate to the previous dose level for the next cohort. There will be no de-escalation from Dose Level 1. Intrapatient dose escalation is not permitted.
Dose escalation is not permitted unless 2 or more patients have complete DLT information through the first cycle in any given dose level. Dose escalation will be determined by using a mCRM with a target DLT rate of 30% and an equivalence interval of 20% to 35%, and with dose escalation-with-overdose-control (EWOC) and no dose skipping.
Patients will be assigned to a cohort that is actively enrolling. Dose escalation will be performed in each combination following the completion of one cycle of treatment. Safety assessments including adverse events (AEs) and laboratory values will be closely monitored for all enrolled patients in order to identify any DLTs. A single MTD/RDE will be defined; a disease-specific MTD/RDE will not be established.
The mCRM will be implemented for DE under the oversight of a Dose Escalation Steering Committee (DESC). The DESC will confirm each escalating dose level after reviewing all available safety data. PK data from patients in that dose level and prior dose levels may also inform decision making. The DESC may halt dose escalation prior to determining the MTD based on emerging PK, PD, toxicity or response data.
Additional patients may be included at any dose level to further assess the safety and
tolerability if at least 1 patient in the study has achieved a partial response or better, or if further evaluation of PK or PD data is deemed necessary by the DESC to determine the RDE.
Dose Escalation will be stopped after 3 cohorts (or at least 6 patients) are consecutively assigned to the same dose level. If the MTD is not reached, the recommended dose for expansion (RDE) will be determined. Prior to the determination of the MTD/RDE a minimum of 6 patients must have been treated with the combination.
It is intended that paired tumor biopsies will be obtained from patients during dose escalation. Analysis of these biopsies will contribute to a better understanding of the relationship between the dose and the pharmacodynamic activity of the combination.
Safety Oversight by the Dose Escalation Steering Committee
A DESC comprised of ADC Therapeutics and the investigators will review patient safety on an ongoing basis during the DE to determine if the dose escalation schedule prescribed by the mCRM warrants modification. In addition to safety observations, PK and/or PD data may also inform decision making. Intermediate doses may be assigned after agreement between ADC Therapeutics and investigators. The DESC may continue to provide oversight during Part 2. No formal Data Safety Monitoring Board (DSMB) will be used.
Dose expansion part
Once the MTD/RDE has been declared, dose expansion part may begin. The main objective of the expansion part is to further assess the safety and tolerability of the study treatment at the MTD/RDE and to gain a preliminary understanding of the efficacy of the combination compared to historical single agent efficacy data.
An important exploratory objective is to assess changes in the immune infiltrate in tumor in response to treatment. This will be assessed in paired tumor biopsies collected from patients, with a minimum of ten evaluable biopsy pairs (biopsy specimens must contain sufficient tumor for analysis) in patients treated at the MTD/RDE. If this is not feasible, collection of these biopsies may be stopped. A minimum of 10 to 20 patients are planned to be treated in each investigational arm,
Several different investigational arms will open, one per disease. A total of nine investigational arms may be run in the dose expansion. Should enrollment for any of these groups not be feasible, then enrollment to that group may be closed before the 10 to 20 patients target is met.
In each treatment group a maximum of approximately six patients who have received and progressed on prior single administration (i.e. not in combination) PARP inhibitor therapy will be allowed to be treated. This number may be increased if a combination shows promise of overcoming resistance to prior treatment with single administration PARP inhibitor.
Patient Population
The study will be conducted in adult patients with advanced Disease A, Disease B or Disease C as outlined above. The investigator or designee must ensure that only patients who meet all the following inclusion and none of the exclusion criteria are offered treatment in the study.
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Written informed consent must be obtained prior to any procedures
2. Age 18 years.
3. Patients with advanced/metastatic cancer, with measurable disease as determined by RECIST version 1.1 , who have progressed despite standard therapy or are intolerant to standard therapy, or for whom no standard therapy exists. Patients must fit into one of the following groups:
• Disease A
• Disease B
• Disease C
4. ECOG Performance Status 0 - 1 (or 2 TBC)
5. TBC: Patient must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Patient must be willing to undergo a new tumor biopsy at baseline, and again during therapy on this study.
6. Prior therapy with the PARP inhibitor or related compounds (i.e. same MOA) is allowed
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. History of severe hypersensitivity reactions to other mAbs (OR to same backbone mAb as in ADC OR to same IO mAb if applicable)
2. Known history of positive serum human ADA to backbone of mAb as in ADC
3. Central Nervous System (CNS) disease only (if applicable)
4. Symptomatic CNS metastases or evidence of leptomeningeal disease (brain MRI or previously documented cerebrospinal fluid (CSF) cytology)
> Previously treated asymptomatic CNS metastases are permitted provided that the last treatment (systemic anticancer therapy and-or local radiotherapy) was completed >= 8 weeks prior to 1st day of dosing, except usage of low dose steroids on a taper is allowed)
> Patients with discrete dural metastases are eligible.
5. Patient having out of range laboratory values defined as:
• Serum creatinine <= 1.5 x ULN. If serum creatinine > 1.5, the creatinine clearance (calculated using Cockcroft-Gault formula, or measured) must be >
60 mL/min/1 ,73m2 for a patient to be eligible
• Total bilirubin > 1.5 x ULN, except for patients with Gilbert's syndrome who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN
• Alanine aminotransferase (ALT) > 3 x ULN, except for patients that have tumor involvement of the liver, who are excluded if ALT > 5 x ULN
• Aspartate aminotransferase (AST) > 3 x ULN, except for patients that have tumor involvement of the liver, who are excluded if AST > 5 x ULN
• Absolute neutrophil count< 1.0 x 10e9/L
• Platelet count< 75 x 10e9/L
• Hemoglobin (Hgb) < 8 g/dL
• Potassium, magnesium, calcium or phosphate abnormality > CTCAE grade 1 despite appropriate replacement therapy Impaired cardiac function or clinically significant cardiac disease, including any of the following:
• Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (NYHA grade III or IV) or uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) 160 mm Hg and/or Diastolic Blood Pressure (DBP) 100 mm Hg, with or without anti-hypertensive medication.
• QTcF >470 msec for females or >450 msec for males on screening ECG using Fridericia's correction, congenital long QT syndrome
• Acute myocardial infarction or unstable angina pectoris < 3 months (months prior to study entry
• Clinically significant valvualr disease with documented compromise in cardiac function
• Symptomatic pericarditis
• History of or ongoing documented cardiomyopathy
• Left Ventricular Ejection Fraction (LVEF) <40%, as determined by echocardiogram (ECHO) or Multi gated acquisition (MUGA) scan
• History or presence of any clinically significant cardiac arrhythmias, e.g. ventricular, supraventricular, nodal arrhythmias, or conduction abnormality (TBC qualifier: ... requiring a pacemaker or not controlled with medication)
• Presence of unstable atrial fibrillation (ventricular response rate> 100 bpm).
> NOTE: Patients with stable atrial fibrillation can be enrolled provided they do not meet other cardiac exclusion criteria.
• Complete left bundle branch block (LBBB), bifascicular block
• Any clinically significant ST segment and/or T-wave abnormalities Toxicity attributed to prior IO therapy that led to discontinuation of therapy. Adequately treated patients for drug-related skin rash or with replacement therapy for endocrinopathies are not excluded, provided these toxicities did not lead to the discontinuation of prior treatment. Patients with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic
treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll, provided the trigger can be avoided. Human Immunodeficiency Virus (HIV), or active Hepatitis B (HBV) or Hepatitis
C (HCV) virus infection
> Testing is not mandatory to be eligible. Testing for HCV should be considered if the patient is at risk for having undiagnosed HCV (e.g. history of injection drug use). Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type. Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity, e.g. mitomycin C and nitrosoureas, 4 weeks is indicated as washout period. For patients receiving anticancer immunotherapies such as CTLA-4 antagonists, 6 weeks is indicated as the washout period. Active diarrhea CTCAE grade 2 or a medical condition associated with chronic diarrhea (such as irritable bowel syndrome, inflammatory bowel disease) Presence of 2: CTCAE grade 2 toxicity (except alopecia, peripheral neuropathy and ototoxicity, which are excluded if >= CTCAE grade 3) due to prior cancer therapy. Active infection requiring systemic antibiotic therapy. Active ulceration of the upper Gl tract or Gl bleeding Active bleeding diathesis or on oral anti-vitamin K medication (except low-dose warfarin and aspirin or equivalent, as long as the INR <= 2.0) Active autoimmune disease, motor neuropathy considered of autoimmune origin, and other CNS autoimmune disease Patients requiring concomitant immunosuppressive agents or chronic treatment with corticoids except:
> replacement dose steroids in the setting of adrenal insufficiency
> topical, inhaled, nasal and ophthalmic steroids are allowed Use of any live vaccines against infectious diseases (e.g. influenza, varicella, pneumococcus) within 4 weeks of initiation of study treatment (NB the use of live vaccines is not allowed through the whole duration of the study) Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GMCSF, M- CSF) < 2 weeks prior start of study drug. An erythroid stimulating agent is allowed as long as it was initiated at least 2 weeks prior to the first dose of study treatment. Major surgery within 2 weeks of the first dose of study treatment (NB
mediastinoscopy, insertion of a central venous access device, or insertion of a feeding tube are not considered major surgery). Radiotherapy within 2 weeks of the first dose of study drug, except for palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tun 1 or mass. To allow for assessment of response to treatment, patients must have remaining measurable disease that has not been irradiated Participation in an interventional, investigational study within 2 weeks of the first dose of study treatment. Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results. Sexually active males unless they use a condom during intercourse while taking drug and for 90 days after stopping study treatment and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. Pregnant or lactating women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. In rare cases of an endocrine-secreting tumor, hCG levels may be above normal limits but with no pregnancy in the patient. In these cases, there should be a repeat serum hCG test (with a non-rising result) and a vaginal/pelvic ultrasound to rule out pregnancy. Upon confirmation of results and discussion with the Medical representative, these patients may enter the study. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during study treatment and for 90 days after the last any dose of study treatment. Highly effective contraception methods include:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
• Male sterilization (at least 6 months prior to screening). For female patients on the study the vasectomized male partner should be the sole partner for that patient.
• Use of oral (estrogen and progesterone), injected or implanted combined hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (I US) or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or
transdermal hormone contraception.
> In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
> Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
Dose-Limiting Toxicities and Dose modification guidelines
A dose-limiting toxicity (DLT) is defined as any of the following events thought to be at least possibly related to ADC per investigator judgment that occurs during the 21-day DLT evaluation period. Toxicity that is clearly and directly related to the primary disease or to another etiology is excluded from this definition.
DLT Definitions
A hematologic DLT is defined as:
■ Grade 3 or 4 febrile neutropenia or neutropenic infection
■ Grade 4 neutropenia lasting >7 days
■ Grade 4 thrombocytopenia
■ Grade 3 thrombocytopenia with clinically significant bleeding, or Grade 3 thrombocytopenia requiring a platelet transfusion
■ Grade 3 anemia that requires transfusion
■ Grade 4 anemia
A non-hematologic DLT is defined as:
■ Grade 4 non-hematologic toxicity
■ Grade 3 non-hematologic toxicity lasting >3 days despite optimal supportive care or medical intervention
■ A case of Hy’s law (AST and/or ALT > 3x ULN and bilirubin > 2x ULN. and without initial findings of cholestasis (serum alkaline phosphatase (ALP) activity < 2x ULN) and no other reason that could explain the combination of increased transaminases and serum total bilirubin, such as viral hepatitis A, B, or C, preexisting or acute liver disease, or another drug capable of causing the observed injury)
■ Grade 3 or higher hypersensitivity/infusion-related reaction (regardless of premedication). A grade 3 hypersensitivity / infusion-related reaction that resolves within 8 hours after onset with appropriate clinical management does not qualify as a DLT.
■ LVEF decrease to < 40% or >20% decrease from baseline
■ Grade 4 tumor lysis syndrome (Grade 3 TLS will not constitute DLT unless it leads to irreversible end-organ damage)
The following conditions are not considered non-hematologic DLT:
• Grade 3 fatigue for < 7 days
• Grade 3 diarrhea, nausea, or vomiting in the absence of premedication that responds to therapy and improves by at least 1 grade within 3 days for Grade 3 events or to < Grade 1 within 7 days.
• AST or ALT elevation > 5 x ULN but < 8 x ULN, without concurrent elevation in bilirubin, that downgrades to < Grade 2 within 5 days after onset.
• Grade 3 serum lipase or serum amylase for < 7 days if without clinical signs or symptoms of pancreatitis
Patients who experience a DLT that resolves or stabilizes with appropriate medical management may continue treatment at the discretion of the investigator in consultation with the sponsor.
Dose modifications
Guidelines for management of specific toxicities are detailed in the table below. For management of events not specified in the tables, the following may serve as a guidance to investigators:
Example 3: n vivo combination study of ADCT-901 and Olaparib in BRCA1 mut/BRCA2 wt, ovarian cancer PDX
Methods
Luminescent cell viability assay and IC50 calculation on cell lines exposed (120 h) to increasing ADCxKAAGI concentrations. Synergy at 120h was assessed by Chou- Talalay combination index (Cl) (synergism CKO.9, additive CKO.9-1.1 , antagonism/no benefit Cl> 1.1) on 3 cancer cell lines, ovarian cancer (SK-OV-3), breast cancer (MDA-MB-231) and renal cancer (SN12C).
Results
ADCxKAAGI was combined in SK-OV-3, MDA-MB-231 and SN12C cell lines with PARP inhibitor olaparib. Synergism was achieved in SK-OV-3 cell line combining ADCxKAAGI with olaparib. Additive effect was observed in MDA-MB-231 and SN12C cell lines.
Data are shown in the tables below.
Conclusion
The in vitro data demonstrates that the combination of ADCxKAAGI and olaparib is beneficial in 3 cell lines that do not carry BRCA mutations. The data demonstrate conditions under which a synergistic therapeutic effect can be obtained. This is consistent with the therapeutic benefit observed in BRCA mutation carrying subjects (see Example 1) extending to subjects not carrying BRCA mutations.
Cell line: MDA-MB-231
Claims
CLAIMS 1. An anti-KAAG1 ADC for use in a method of treating a disorder in an individual, the method comprising administering to the individual an effective amount of an anti-KAAG1 ADC and a PARP inhibitor; wherein the anti-KAAG1 ADC is a conjugate of formula L - (DL)p, where DL is of formula I or II: I II
wherein: L is an antibody (Ab) that binds to KAAG1; when there is a double bond present between C2’ and C3’, R12 is selected from the group consisting of: (ia) C5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, carboxy, ester, C1-7 alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene; (ib) C1-5 saturated aliphatic alkyl; (ic) C3-6 saturated cycloalkyl;
wherein each of R21, R22 and R23 are independently selected from H, C1- 3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R12 group is no more than 5; R25b
, wherein one of R25a and R25b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and
(if)
, where R 24 is selected from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; when there is a single bond present between C2’ and C3’, R12 is
, where R 26a and R 26b are independently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester; or, when one of R26a and R26b is H, the other is selected from nitrile and a C1-4 alkyl ester; R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR’, nitro, Me3Sn and halo; where R and R’ are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR’, nitro, Me3Sn and halo; R″ is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, NRN2 (where RN2 is H or C1-4 alkyl), and/or aromatic rings, e.g. benzene or pyridine; Y and Y’ are selected from O, S, or NH; R6’, R7’, R9’ are selected from the same groups as R6, R7 and R9 respectively; [Formula I] RL1’ is a linker for connection to the antibody (Ab); R11a is selected from OH, ORA, where RA is C1-4 alkyl, and SOzM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; R20 and R21 either together form a double bond between the nitrogen and carbon atoms to which they are bound or; R20 is selected from H and RC, where RC is a capping group; R21 is selected from OH, ORA and SOzM; when there is a double bond present between C2 and C3, R2 is selected from the group consisting of: (ia) C5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, carboxy, ester, C1-7 alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene; (ib) C1-5 saturated aliphatic alkyl; (ic) C3-6 saturated cycloalkyl;
, wherein each of R11, R12 and R13 are independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R2 group is no more than 5;
, wherein one of R15a and R15b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and (if)
, where R14 is selected from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; when there is a single bond present between C2 and C3, R2 is , where R16a and R16b are independently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester; or, when one of R16a and R16b is H, the other is selected from nitrile and a C1-4 alkyl ester; [Formula II] R22 is of formula IIIa, formula IIIb or formula IIIc:
where A is a C5-7 aryl group, and either (i) Q1 is a single bond, and Q2 is selected from a single bond and -Z-(CH2)n-, where Z is selected from a single bond, O, S and NH and n is from 1 to 3; or (ii) Q1 is -CH=CH-, and Q2 is a single bond;
where Q is selected from O-RL2’, S-RL2’ and NRN-RL2’, and RN is selected from H, methyl and ethyl X is selected from the group comprising: O-RL2’, S-RL2’, CO2-RL2’, CO-RL2’, NH-C(=O)-RL2’, NHNH-RL2’, CONHNH-RL2’,
, NRNRL2’, wherein RN is selected from the group comprising H and C1-4 alkyl; RL2’ is a linker for connection to the antibody (Ab);
R10 and R11 either together form a double bond between the nitrogen and carbon atoms to which they are bound or; R10 is H and R11 is selected from OH, ORA and SOzM; R30 and R31 either together form a double bond between the nitrogen and carbon atoms to which they are bound or; R30 is H and R31 is selected from OH, ORA and SOzM.
3. The anti-KAAG1 ADC for use according to either one of claims 1 or 2, wherein the anti-KAAG1 ADC comprises an antibody having a VH domain comprising a VH CDR1, a VH CDR2, and a VH CDR3, wherein the antibody comprises the CDR sequences of the VH domain having the sequence according to SEQ ID NO: 1.
4. The anti-KAAG1 ADC for use according to claim 3, wherein the antibody further comprises a VL domain comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein the antibody comprises the CDR sequences of the VL domain having the sequence according to SEQ ID NO: 2. 5. The anti-KAAG1 ADC for use according to either one of claims 1 or 2, wherein the anti-KAAG1 ADC comprises an antibody having a VH domain comprising a VH CDR1 with the amino acid sequence of SEQ ID NO.
5, a VH CDR2 with the amino acid sequence of SEQ ID NO.6, and a VH CDR3 with the amino acid sequence of SEQ ID NO.7.
6. The anti-KAAG1 ADC for use according to claim 5, wherein the antibody further comprises a VL domain comprising a VL CDR1 with the amino acid sequence of SEQ ID NO.8, a VL CDR2 with the amino acid sequence of SEQ ID NO.9, and a VL CDR3 with the amino acid sequence of SEQ ID NO.10.
7. The anti-KAAG1 ADC for use according to any one of claims 1 to 6, wherein the anti-KAAG1 ADC comprises an antibody having a VH domain having the sequence according to SEQ ID NO: 1.
8. The anti-KAAG1 ADC for use according to claim 7, wherein the anti-KAAG1 ADC further comprises an antibody having a VL domain having the sequence according to SEQ ID NO: 2.
9. The anti-KAAG1 ADC for use according to any one of claims 1 to 8, wherein the anti-KAAG1 ADC is ADCT-901.
10. The anti-KAAG1 ADC for use according to any one of claims 1 to 9, wherein the treatment comprises administering the anti-KAAG1 ADC before the PARP inhibitor, simultaneous with the PARP inhibitor, or after the PARP inhibitor.
11. The anti-KAAG1 ADC for use according to any one of claims 1 to 10, wherein the treatment further comprises administering a chemotherapeutic agent.
12. The anti-KAAG1 ADC for use according to any one of claims 1 to 11, wherein the individual is human.
13. The anti-KAAG1 ADC for use according to any one of claims 1 to 12, wherein the individual has, or has been has been determined to have, a cancer which expresses KAAG1 or KAAG1+ tumour-associated non-tumour cells, such as KAAG1+ infiltrating cells.
14. The anti-KAAG1 ADC for use according to any one or claims 1 to 13, wherein the individual is refractory to treatment, or further treatment, with the PARP inhibitor.
15. The anti-KAAG1 ADC for use according to any one or claims 1 to 14, wherein the disorder is a proliferative disease.
16. The anti-KAAG1 ADC for use according to claim 15, wherein the disorder is cancer.
17. The anti-KAAG1 ADC for use according to any one of claims 1 to 16, wherein the individual has, or has been has been determined to have, a disorder characterised by the presence of a neoplasm comprising both KAAG1+ve and KAAG1-ve cells.
18. The anti-KAAG1 ADC for use according to any one of claims 1 to 17, wherein the individual has, or has been has been determined to have, a disorder characterised by the presence of a neoplasm comprising, or composed of, KAAG1-ve neoplastic cells.
19. The anti-KAAG1 ADC for use according to any one of claims 15 to 18, wherein the disorder is a solid tumour.
20. The anti-KAAG1 ADC for use according to any one of claims 16 to 19, wherein the disorder is selected from the group comprising: lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma,
prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, and sarcoma.
21. The anti-KAAG1 ADC for use according to any one of claims 16 to 19, wherein the disorder is selected from the group comprising: ovarian, breast, prostate, renal cancer, cholangiacarcinoma, and sarcoma.
22. The anti-KAAG1 ADC for use according to any one of claims 16 to 21, wherein the cancer is a BRCA-associated cancer.
23. The anti-KAAG1 ADC for use according to claim 22, wherein the BRCA-associated cancer has a mutation in a BRCA1 and/or BRCA2 gene.
24. The anti-KAAG1 ADC for use according to claim 22, wherein the BRCA-associated cancer is characterised by cancer cells having a mutation in a BRCA1 and/or BRCA2.
25. The anti-KAAG1 ADC for use according to any one of claims 22 to 24, wherein the BRCA-associated cancer is characterised by cancer cells exhibiting loss of BRCA1 or BRCA2 function
26. The anti-KAAG1 ADC for use according to any one of claims 1 to 25, wherein the individual is selected for treatment if they have a mutation in a BRCA1 and/or BRCA2 gene.
27. The anti-KAAG1 ADC for use according to any one of claims 1 to 26, wherein the individual is selected for treatment if they have BRCA-associated cancer.
28. The anti-KAAG1 ADC for use according to any one of claims 1 to 21, wherein the cancer is not a BRCA-associated cancer.
29. The anti-KAAG1 ADC for use according to any one of claims 1 to 21 or 28, wherein the individual is selected for treatment if they have a cancer that is not a BRCA-associated cancer.
30. The anti-KAAG1 ADC for use according to any one of claims 1 to 29, wherein the individual is selected for treatment if they are refractory to treatment, or further treatment, with the PARP inhibitor.
31. The anti-KAAG1 ADC for use according to any one of claims 1 to 30, wherein the PARP inhibitor is selected from the group consisting of: Olaparib (ABT-199), CEP-9722, BMN-673/talazoparib, Rucaparib, Iniparib, Veliparib and Niraparib, 3-Aminobenzamide, or E7016.
32. The anti-KAAG1 ADC for use according to any one of claims 1 to 30, wherein the PARP inhibitor is Olaparib.
33. The anti-KAAG1 ADC for use according to any one of claims 1 to 30, wherein the PARP inhibitor is talazoparib.
34. A method of treatment as defined in any one of claims 1 to 33.
35. Use of an anti-KAAG1 ADC in the manufacture of a medicament for treating a disorder in an individual, wherein the treatment is as defined in any one of claims 1 to 33.
36. A composition comprising an anti-KAAG1 ADC and a PARP inhibitor, wherein the anti-KAAG1 ADC and PARP inhibitor are defined according to any one of claims 1 to 33.
37. The composition of claim 36 for use in a method of treatment, wherein the treatment is as defined in any one of claims 1 to 33.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
WO2007044515A1 (en) | 2005-10-07 | 2007-04-19 | Exelixis, Inc. | Azetidines as mek inhibitors for the treatment of proliferative diseases |
US9393392B2 (en) | 2012-08-14 | 2016-07-19 | Sanfreud Corporation | Poultice applicator |
WO2018146199A1 (en) * | 2017-02-08 | 2018-08-16 | Adc Therapeutics Sa | Pyrrolobenzodiazepine-antibody conjugates |
-
2020
- 2020-08-05 GB GBGB2012161.2A patent/GB202012161D0/en not_active Ceased
-
2021
- 2021-08-05 WO PCT/EP2021/071861 patent/WO2022029223A1/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
WO2007044515A1 (en) | 2005-10-07 | 2007-04-19 | Exelixis, Inc. | Azetidines as mek inhibitors for the treatment of proliferative diseases |
US9393392B2 (en) | 2012-08-14 | 2016-07-19 | Sanfreud Corporation | Poultice applicator |
WO2018146199A1 (en) * | 2017-02-08 | 2018-08-16 | Adc Therapeutics Sa | Pyrrolobenzodiazepine-antibody conjugates |
Non-Patent Citations (35)
Title |
---|
"CAS", Database accession no. 283173-50-2 |
"Genbank", Database accession no. AAA60137 |
"NCBI", Database accession no. →24958200 |
"Swiss-Prot", Database accession no. P09874 |
ANDRABI, PNAS, 2014 |
ANGEW CHEM. INTL. ED. ENGL., vol. 33, 1994, pages 183 - 186 |
ANONYMOUS: "A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of ADCT-901 in Participants With Selected Advanced Solid Tumors - Tabular View - ClinicalTrials.gov", 22 July 2021 (2021-07-22), XP055860713, Retrieved from the Internet <URL:https://clinicaltrials.gov/ct2/show/record/NCT04972981> [retrieved on 20211112] * |
ANONYMOUS: "ADCT-901: PBD-Based ADC Targeting KAAG1", 6 September 2019 (2019-09-06), XP055860707, Retrieved from the Internet <URL:https://www.sec.gov/Archives/edgar/data/1771910/000114036119016305/nt10002526x5_f1.htm> [retrieved on 20211112] * |
BRYANT HE ET AL., NATURE, vol. 434, 2005, pages 913 - 21 |
CARTER, P., NATURE REVIEWS IMMUNOLOGY, vol. 6, 2006, pages 343 - 357 |
CAS , no. 85622-93-1 |
CAS, no. 1820833-75-7 |
CLACKSON ET AL., NATURE, vol. 352, 1991, pages 624 - 628 |
FLYNN ET AL., MOL CANCER THER, 2016 |
HAMANN P., EXPERT OPIN. THER. PATENTS, vol. 15, no. 9, 2005, pages 1087 - 1103 |
J MERSCH ET AL., CANCER, vol. 121, no. 2, 15 January 2015 (2015-01-15), pages 269 - 275 |
JANEWAY, C., TRAVERS, P., WALPORT, M., SHLOMCHIK: "Immuno Biology", 2001, GARLAND PUBLISHING |
KOHLER ET AL., NATURE, vol. 256, 1975, pages 495 |
KOVTUN ET AL., CANCER RES., vol. 66, no. 4, 2006, pages 2328 - 2337 |
KS PEGGS ET AL., CLINICAL AND EXPERIMENTAL IMMUNOLOGY, vol. 157, 2009, pages 9 - 19 |
LAMBERT J., CURRENT OPIN. IN PHARMACOL., vol. 5, 2005, pages 543 - 549 |
LONBERG, CURR. OPINION, vol. 20, no. 4, 2008, pages 450 - 459 |
MARKS ET AL., J. MOL. BIOL., vol. 222, 1991, pages 581 - 597 |
MATEO J ET AL: "A decade of clinical development of PARP inhibitors in perspective", ANNALS OF ONCOLOGY, vol. 30, no. 9, 1 September 2019 (2019-09-01), NL, pages 1437 - 1447, XP055860728, ISSN: 0923-7534, DOI: 10.1093/annonc/mdz192 * |
MILLER ET AL., JOUR. OF IMMUNOLOGY, vol. 170, 2003, pages 4854 - 4861 |
MORRISON ET AL., PROC. NATL. ACAD. SCI. USA, vol. 81, 1984, pages 6851 - 6855 |
PAYNE, G., CANCER CELL, vol. 3, 2003, pages 207 - 212 |
SYRIGOSEPENETOS, ANTICANCER RESEARCH, vol. 19, 1999, pages 605 - 614 |
TRAIL ET AL., CANCER IMMUNOL. IMMUNOTHER., vol. 52, 2003, pages 328 - 337 |
TUTT AN ET AL., COLD SPRING HARB SYMP QUANT BIOL, vol. 70, 2005, pages 139 - 48 |
VAN DEN EYNDE ET AL., J EXP MED, vol. 190, no. 12, 1999, pages 1793 - 1800 |
WU ET AL., NATURE BIOTECH., vol. 23, no. 9, 2005, pages 1137 - 1145 |
XIE ET AL., EXPERT. OPIN. BIOL. THER., vol. 6, no. 3, 2006, pages 281 - 291 |
ZAMMARCHI F ET AL: "Abstract 234: Pre-clinical characterization of 3A4-PL1601, a novel pyrrolobenzodiazepine (PBD) dimer-based antibody-drug conjugate (ADC) directed against KAAG1-expressing malignancies", PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH ANNUAL MEETING 2019, 1 July 2019 (2019-07-01), XP055719462, DOI: 10.1158/1538-7445.AM2019-234 * |
ZHONG H ET AL: "Improved Therapeutic Window in BRCA -mutant Tumors with Antibody-linked Pyrrolobenzodiazepine Dimers with and without PARP Inhibition", MOLECULAR CANCER THERAPEUTICS, vol. 18, no. 1, 23 October 2018 (2018-10-23), US, pages 89 - 99, XP055601713, ISSN: 1535-7163, DOI: 10.1158/1535-7163.MCT-18-0314 * |
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