WO2022248268A1 - Combination therapy - Google Patents
Combination therapy Download PDFInfo
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- WO2022248268A1 WO2022248268A1 PCT/EP2022/063158 EP2022063158W WO2022248268A1 WO 2022248268 A1 WO2022248268 A1 WO 2022248268A1 EP 2022063158 W EP2022063158 W EP 2022063158W WO 2022248268 A1 WO2022248268 A1 WO 2022248268A1
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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
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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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
- 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.
- combination therapies comprising treatment with an anti-DLK1 Antibody Drug Conjugate (anti-DLK1 ADC) and a secondary agent selected from gemcitabine.
- anti-DLK1 ADC anti-DLK1 Antibody Drug Conjugate
- secondary agent selected from gemcitabine.
- a PARP inhibitor and a checkpoint modulator are examples of anti-DLK1 Antibody Drug Conjugate
- Antibody therapy has been established for the targeted treatment of subjects with cancer, immunological and angiogenic disorders.
- Delta-like 1 homolog protein is an EGF-like membrane bound protein consisting of six tandem EGF-like repeats, a juxtamembrane region with a TACE (ADAM17)-mediated cleavage site, a transmembrane domain, and a short intracellular tail.
- DLK1 is strongly expressed during fetal development, but its expression is turned down and highly restricted in adults. Conversely, DLK1 gets re-expressed in several tumours, such as neuroblastoma, hepatocellular carcinoma (HCC), rhabdomyosarcoma, small cell lung cancer, myelodysplastic syndrome and acute myeloid leukemia.
- HCC hepatocellular carcinoma
- rhabdomyosarcoma small cell lung cancer
- myelodysplastic syndrome acute myeloid leukemia.
- DLK1 has been shown to be a marker of cancer stem cells, a subpopulation of cells responsible for tumour initiation, growth, metastasis, and recurrence. DLK1 represents an attractive target for an antibody-drug conjugate (ADC) approach based on its selective expression in a wide range of malignancies and restricted expression in healthy organs, as well as its expression on HCC cancer stem cells.
- ADC antibody-drug conjugate
- an Antibody Drug Conjugate comprising an anti-DLK1 antibody (an anti-DLK1 ADC) in the treatment of, for example, cancer has been established - see, for example, WO2018/146199. Research continues to further improve the efficacy, tolerability, and clinical utility of anti-DLK1 ADCs. To this end, the present authors have considered clinically advantageous combination therapies in which an anti-DLK1 ADC is administered in combination with gemcitabine.
- the present disclosure provides a method for treating a disorder in an individual, the method comprising administering to the individual an anti-DLK1 ADC and a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator.
- the method comprises administering an effective amount of an anti-DLK1 ADC and a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator.
- the method of treatment may further comprise selecting an individual for treatment.
- the individual may be selected for treatment with an anti-DLK1 ADC if he/she has been treated with a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator, if he/she is being treated with a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator, and/or if he/she is refractory to treatment, or further treatment, with a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator.
- 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 anti-DLK1 ADC.
- the method comprises administering an effective amount of the anti-DLK1 ADC.
- the method of treatment may further comprise administering a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator in combination with the anti-DLK1 ADC.
- the treatment may comprise administering the anti-DLK1 ADC before the secondary agent, simultaneous with the secondary agent, or after the secondary agent.
- the disclosed methods may comprise administering a further chemotherapeutic agent to the individual.
- the individual may be human.
- the individual may have a disorder or may have been determined to have a disorder.
- the individual may have cancer or may have been determined to have cancer.
- the individual may have, or have been determined to have, a cancer which expresses DLK1 .
- the cancer may comprise both DLK1+ve and DLK1-ve cancer cells.
- the individual may have, or have been determined to have, DLK1+ve tumour-associated non-tumour cells, such as DLK1+ve infiltrating cells.
- the individual may be undergoing treatment with the secondary agent and/or have previously undergone treatment with the secondary agent.
- the individual may be refractory to treatment, or further treatment, with the secondary agent.
- the neoplasm may be all or part of a solid tumour.
- the neoplasm may be all or part of an advanced solid tumour.
- Solid tumours may be neoplasms, including non- haematological cancers, comprising or composed of DLK1+ve neoplastic cells.
- Solid tumours may be neoplasms, including non-haematological cancers, comprising or composed of DLK1+ve neoplastic cells and DLK1-ve neoplastic cells.
- the solid tumour may be associated with DLK1+ve infiltrating cells.
- Solid tumours may be neoplasms, including non-haematological cancers, infiltrated with DLK1+ve cells.
- the disorder may be a proliferative disease, for example a cancer.
- the disorder may be a cancer such as hepatocellular carcinoma, hepatoblastoma, lung cancer, non small cell lung cancer, small cell lung cancer, breast cancer, gastric cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carcinoma, ovarian cancer, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, hepatocellular carcinoma, rhabdomyosarcoma, cholangiacarcinoma, kidney cancer, renal cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi’s sarcoma, melanoma, neuroblastoma, adrenal gland cancer, adrenocortical carcinoma, pheochromocytoma, paraganglioma, thyroid medullary cancer, thyroid medullary carcinoma, skeletal muscle cancer, liposarcoma, bone-derived cancer glioma, Wilms tumour,
- Cancers of particular interest include myelodysplastic syndrome, acute myeloid leukaemia, hepatoblastoma, small cell lung cancer, colon cancer, neuroblastoma, adrenal gland cancer, pheochromocytoma, paraganglioma and skeletal muscle tumour. More specifically, cancers of particular interest include small cell lung cancer, neuroblastoma, adrenocortical carcinoma, pheochromocytoma and paraganglioma.
- the anti-DLK1 ADC may be as defined in the section herein entitled “Anti- DLK1 ADCs”.
- the anti-DLK1 ADC may be ADCT-701 .
- the present disclosure provides an anti-DLK1 ADC, or a composition comprising an anti-DLK1 ADC, for use in a method of treatment as described herein.
- the anti-DLK1 ADC may be as defined in the section herein entitled “Anti-DLK1 ADCs”.
- the anti-DLK1 ADC may be ADCT-701 .
- the present disclosure provides gemcitabine, or a composition comprising a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator, for use in a method of treatment as described herein.
- the present disclosure provides for the use of an anti-DLK1 ADC and/or a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator 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 anti-DLK1 ADC may be as defined in the section herein entitled “Anti-DLK1 ADCs”.
- the anti-DLK1 ADC may be ADCT-701.
- the individual may be undergoing treatment with a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator and/or have previously undergone treatment with the secondary agent.
- the individual may be refractory to treatment, or further treatment, with the secondary agent.
- the anti-DLK1 ADC may be as defined in the section herein entitled “Anti-DLK1 ADCs”.
- the anti- DLK1 ADC may be ADCT-701 .
- the first composition may be administered before the second composition, simultaneous with the second composition, or after the second composition.
- kits comprising: a first medicament comprising an anti-DLK1 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 secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator.
- kits comprising: a first medicament comprising an anti-DLK1 ADC; a second medicament comprising a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator; 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.
- the disclosure provides a composition comprising an anti-DLK1 ADC and a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator.
- 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 the composition comprising an anti-DLK1 ADC and a secondary agent selected from gemcitabine, a PARP inhibitor and a checkpoint modulator.
- the method comprises administering to the individual an effective amount of the composition comprising an anti-DLK1 ADC and the secondary agent.
- ADCs Antibody Drug Conjugates
- the present disclosure relates to the improved efficacy of combinations of an ADC and a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator.
- 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-proliferative 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 to treatment with an anti-DLK1 ADC disclosed in WO2018/146199, and as herein described.
- DLK1 ADC refers to an ADC in which the antibody component is an anti- DLK1 antibody.
- PBD-ADC refers to an ADC in which the drug component is a pyrrolobenzodiazepine (PBD) warhead.
- anti-DLK1 ADC refers to an ADC in which the antibody component is an anti-DLK1 antibody, and the drug component is a PBD warhead.
- the ADC may comprise a conjugate of formula (I): Ab - (DL) P (I), wherein:
- Ab is an antibody that binds to DLK1 ;
- X is selected from the group comprising: a single bond, -CH2- and -C2H4-; n is from 1 to 8; m is 0 or 1 ;
- R 7 is either methyl or phenyl; when there is a double bond between C2 and C3, R 2 is selected the group consisting of:
- R 21 , R 22 and R 23 are independently selected from H, C1-3 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;
- R 25a and R 25b are 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
- 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 between C2 and C3, R 2 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 C 1-4 alkyl ester; or, when one of R 26a and R 26b is H, the other is selected from nitrile and a C 1-4 alkyl ester; when there is a double bond between C2’ and C3’, R 12 is selected the group consisting of:
- R 31 , R 32 and R 33 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 R 12 group is no more than 5;
- R 35a and R 35b are 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
- R 24 is selected from: H; C 1 -3 saturated alkyl; C 2 -3 alkenyl; C 2 -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 between C ’ and C ’, R 12 is , where R 36a and R 36b are independently selected from H, F, C 1-4 saturated alkyl, C 2 -3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4 alkyl amido and C 1-4 alkyl ester; or, when one of R 36a and R 36b is H, the other is selected from nitrile and a C 1-4 alkyl ester; and p is from 1 to 2.
- 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 2 Drug units (DL) per antibody.
- p represents the average drug loading of the Conjugates in the composition, and p ranges from 1 to 2.
- anti-DLK1 ADC may include any embodiment described in WO2018/146199.
- a preferred embodiment is a conjugate having the structure: wherein the antibody (Ab) comprises (i) a VH domain having the sequence of SEQ ID N0.1 , and (ii) a VL domain having the sequence of SEQ ID NO.2.
- the antibody is an antibody as described herein which has been modified (or further modified) as described in, for example, WO2018/146199.
- the antibody is a humanised, deimmunised or resurfaced version of an antibody disclosed herein.
- a preferred anti-DLK1 ADC for use with the aspects of the present disclosure is ADCT-701 .
- the antibody is an antibody that binds to DLK1 .
- 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 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 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.
- the antibody comprises a VH domain and a VL domain.
- the VH comprises the sequence of SEQ ID N0.1 and the VL domain comprises the sequence of SEQ ID NO.2.
- VH and VL domain(s) may pair so as to form an antibody antigen binding site that binds DLK1 .
- 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 N0.1 paired with 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. 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.
- 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. In some embodiments the antibody is an intact antibody comprising two heavy chains having the sequence of SEQ ID N0.11 , each paired with a light chain 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, WO2018/146199.
- the antibody is a humanised, deimmunised or resurfaced version of an antibody disclosed herein.
- the antibody has been modified using GlycoConnect, or a similar technology, to trim N-linked glycans at Asn-297 (or its equivalent) with an endoglycosidase back to a core N-acetylglucosamine (GlcNAc) residue.
- GlcNAc N-acetylglucosamine
- a subsequent procedure using a b-1-4- galactosyltransferase and a sugar derivative e.g. a UDP-GalNAc derivative containing a click chemistry reactive group, such as UDP-N-azidoacetylgalactosamine
- results in the addition of a further sugar such as N-acetylgalactosamine (GalNAc).
- ADCT-701 is an antibody drug conjugate composed of a humanized antibody against human DLK1 attached to a pyrrolobenzodiazepine (PBD) warhead via a cleavable linker.
- PPD pyrrolobenzodiazepine
- the mechanism of action of ADCT-701 depends on DLK1 binding.
- the DLK1 specific antibody targets the antibody drug conjugate (ADC) to cells expressing DLK1 .
- the ADC 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.
- ADCT-701 has the chemical structure:
- the antibody (Ab) represents Antibody HuBa-1-3-d having the VH and VL sequences SEQ ID NO. 1 and SEQ ID NO. 2, respectively.
- ADCT-701 is synthesised as described in WO2018/146199 and typically has a DAR (Drug to Antibody Ratio) of about 1.9.
- the drug linker is typically conjugated to the antibody through the sidechain of the N-linked glycosylation site asparagine 297 via GlcNAc-GalNAc.
- binds DLK1 is used to mean the antibody binds DLK1 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 DLK1 with an association constant (K a ) at least 2, 3, 4, 5, 10, 20, 50, 100 , 200 , 500, 1000 , 2000 , 5000, 10 4 , 10 s or 10 6 -fold higher than the antibody’s association constant for BSA, when measured at physiological conditions.
- the antibodies of the invention can bind DLK1 with a high affinity.
- the antibody can bind DLK1 with a KD equal to or less than about 10 6 M, such as 1 x 10 _e , 10 7 , 10 8 , 10 -9 , 10 -10 , 10 11 , 10 12 , 10- 13 or
- DLK1 is member of the EGF-like family of homeotic proteins.
- the DLK1 polypeptide corresponds to Genbank accession no. CAA78163, version no. CAA78163.1 , record update date: Feb 2, 2011 10:34 AM (SEQ ID NO.12).
- the nucleic acid encoding DLK1 polypeptide corresponds to Genbank accession no. Z12172, version no Z12172.1 , record update date: Feb 2, 2011 10:34 AM.
- Antibody-drug conjugates including those with a PBD warhead, may be particularly suited as combination partners because they are more targeted compared to conventional chemotherapy.
- Gemcitabine is a broad-spectrum antimetabolite and deoxycytidine analogue with antineoplastic activity. Upon administration, gemcitabine is converted into the active metabolites difluorodeoxycytidine diphosphate (dFdCDP) and difluorodeoxycytidine triphosphate (dFdCTP) by deoxycytidine kinase. dFdCTP competes with deoxycytidine triphosphate (dCTP) and is incorporated into DNA. This locks DNA polymerase thereby resulting in masked termination during DNA replication.
- dFdCDP difluorodeoxycytidine diphosphate
- dFdCTP difluorodeoxycytidine triphosphate
- dFdCDP inhibits ribonucleotide reductase, thereby decreasing the deoxynucleotide pool available for DNA synthesis.
- the reduction in the intracellular concentration of dCTP potentiates the incorporation of dFdCTP into DNA.
- Gemcitabine has shown activity in a variety of solid tumors and has been approved for the treatment of non-small cell lung cancer, pancreatic, bladder, and breast cancer. Recent data showed that gemcitabine is also active against ovarian cancer. Gemcitabine is reported to have a good toxicity profile, with myelosuppression being the most common side effect, while non-hematological events are relatively uncommon (Toschi et al., 2005, Future Oncology, Vol.1 (1), pp.7-17).
- PBDs are a class of naturally occurring anti-tumour 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 tumour cell death. As PBD dimers cross-link DNA in a covalent fashion, combining them with other agents that interfere with DNA synthesis via a different mechanism, such as gemcitabine, is likely to provide a benefit. Tumours expressing DLK1 can be targeted for killing by this mechanism by using a PBD-based DLK1 -targeting ADC, such as ADCT-701 , in combination with Gemcitabine.
- a PBD-based DLK1 -targeting ADC such as ADCT-701
- An anti-DLK-1-ADC such as ADCT-701 and Gemcitabine can be used to target and directly kill DLK1 (+) cancer cells.
- DLK-1 (+) tumour cells DLK-1 (-) tumour cells in close proximity to DLK-1 (+) tumour cells will potentially be killed by the bystander mechanism of the PBD-dimer released after cell kill of DLK-1 (+) cells and Gemcitabine. The resulting release of tumour associated antigens from cells that are killed with the PBD dimer will trigger the immune system.
- the combination therapy disclosed herein is effective against cancers which do not express DLK1 .
- DLK1 is expressed on immune cells that infiltrate the local tumour environment and which can have a suppressive impact on the innate immune response against the tumour. Examples are Tregs, NK cells, DC cells or macrophages.
- An anti-DLK-1-ADC such as ADCT-701 can be used to target these immune cells, which on the one hand will kill the immune suppressive cells, boosting the immune response. Also, killing of the immune cells by ADCT-701 will release local PBD warhead which is able to kill subsequent neighbouring cells via bystander kill.
- tumours not expressing DLK1 can be killed by targeting immune cells in the local tumour environment. Also, targeting DLK1 negative tumour cells killed by PBD released from neighbouring immune cells will induce immunogenic cell death further strengthening the anti-tumour immune response.
- a panel of solid tumour-derived cell lines will be treated with a range of concentration of each ADC and gemcitabine.
- 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 Poly (adenosine diphosphate [ADP]) ribose polymerase
- ADP adenosine diphosphate
- PARP-1 is the most abundant and best characterised protein of this group.
- PARP-1 inhibitors PARPi
- Olaparib CEP- 9722
- Talazoparib Rucaparib
- Iniparib Veliparib
- Niraparib Niraparib
- Pamiparib 3-Aminobenzamide and E7016
- 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 auto-modification 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.
- poly (ADP-ribose) or PAR polymeric adenosine diphosphate ribose
- Target enzymes include DNA ligase III (Liglll), DNA polymerase beta (ro ⁇ b), and scaffolding proteins such as X-ray cross-complementing gene 1 (XRCC1). After repairing, the PAR chains are degraded via Poly(ADP-ribose) glycohydrolase (PARG).
- PARG Poly(ADP-ribose) glycohydrolase
- 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).
- 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.
- PARP is inactivated by caspase-3 cleavage during programmed cell death.
- PBDs are a class of naturally occurring anti-tumour 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 tumour 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 tumours as opposed to normal tissues.
- PBD-based ADCs with PARPi including but not limited to Olaparib, CEP-9722, Talazoparib, Rucaparib, Iniparib, Veliparib, Niraparib, Pamiparib, 3-Aminobenzamide and E7016
- PARPi including but not limited to Olaparib, CEP-9722, Talazoparib, Rucaparib, Iniparib, Veliparib, Niraparib, Pamiparib, 3-Aminobenzamide and E7016
- Tumours expressing DLK1 can be targeted for killing by this mechanism by using a PBD-based DLK1 -targeting ADC, such as ADCT-701 , in combination with a PARP inhibitor (including but not limited to Olaparib, CEP-9722, Talazoparib, Rucaparib, Iniparib, Veliparib, Niraparib, Pamiparib, 3- Aminobenzamide and E7016).
- a PARP inhibitor including but not limited to Olaparib, CEP-9722, Talazoparib, Rucaparib, Iniparib, Veliparib, Niraparib, Pamiparib, 3- Aminobenzamide and E7016).
- An anti-DLK-1-ADC such as ADCT-701 can be used to target and directly kill DLK1 (+) cancer cells.
- DLK-1 (+) tumour cells DLK-1 (-) tumour cells in close proximity to DLK-1 (+) tumour cells will potentially be killed by the bystander mechanism of the PBD-dimer released after cell kill of DLK- 1 (+) cells. The resulting release of tumour associated antigens from cells that are killed with the PBD dimer will trigger the immune system.
- the combination therapy disclosed herein is effective against cancers which do not express DLK1 .
- DLK1 is expressed on immune cells that infiltrate the local tumour environment and which can have a suppressive impact on the innate immune response against the tumour. Examples are Tregs, NK cells, DC cells or macrophages.
- An anti-DLK-1-ADC such as ADCT-701 can be used to target these immune cells, which on the one hand will kill the immune suppressive cells, boosting the immune response. Also, killing of the immune cells by an anti-DLK-1-ADC such as ADCT-701 will release local PBD warhead which is able to kill subsequent neighbouring cells via bystander kill.
- tumours not expressing DLK1 can be killed by targeting immune cells in the local tumour environment.
- target negative tumour cells killed by PBD released from neighbouring immune cells will induce immunogenic cell death further strengthening the anti-tumour immune response.
- a panel of solid tumour-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 which 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%.
- Olaparib is a particularly preferred PARPi for use in the methods of the present disclosure.
- 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.
- Immune checkpoint molecules are modulators of the anti-tumour immune response. Their interaction may activate or inhibit either activating or inhibitory immune signalling pathways. Immune checkpoint molecules may be present a variety of cell types, including but not limited to T cells, antigen-presenting cells and tumour cells. Examples of inhibitory immune checkpoint molecules include PD-1 and CTLA-4. Examples of activatory immune checkpoint molecules include 0X40 and GITR.
- checkpoint modulator means any chemical compound or biological molecule that stimulates an immune reaction through inhibition of inhibitory checkpoint molecule signalling (including but not limited to PD-1 signalling, CTLA-4 signalling, LAG-3 signalling, TIM-3 signalling, or TIGIT signalling) or through activation of activatory checkpoint signalling (including but not limited to 0X40 signalling and GITR signalling).
- inhibitory checkpoint molecule signalling including but not limited to PD-1 signalling, CTLA-4 signalling, LAG-3 signalling, TIM-3 signalling, or TIGIT signalling
- activatory checkpoint signalling including but not limited to 0X40 signalling and GITR signalling.
- a “checkpoint modulator” may interact with an immune checkpoint molecule, or a ligand to which an immune checkpoint molecule binds, to inhibit checkpoint molecule signalling.
- inhibition of PD-1 signalling can be achieved using a checkpoint modulator which targets PD-1 (e.g. Nivolumab) and/or a checkpoint modulator which targets PD-L1 (e.g. Atezolumab).
- a “checkpoint modulator” may interact with an immune checkpoint molecule, or a ligand to which an immune checkpoint molecules binds, to stimulate checkpoint molecule signalling.
- activation of 0X40 signalling can be achieved using a checkpoint modulator which activates the costimulatory molecule 0X40, such as an 0X40 agonist.
- Programmed death receptor I is an immune-inhibitory receptor that is primarily expressed on activated T and B cells. Interaction with its ligands has been shown to attenuate T-cell responses both in vitro and in vivo. Blockade of the interaction between PD1 and one of its ligands, PD-L1 , has been shown to enhance tumour-specific CD8+ T-cell immunity and may therefore be helpful in clearance of tumour cells by the immune system.
- PD1 (encoded by the gene Pdcdl) is an Immunoglobulin superfamily member related to CD28, and CTLA-4. PD1 has been shown to negatively regulate antigen receptor signalling upon engagement of its ligands (PD-L1 and/or PD-L2). The structure of murine PD1 has been solved as well as the cocrystal structure of mouse PD1 with human PD-L1 (Zhang, X., et al., (2004) Immunity 20: 337-347; Lin, et al., (2008) PNAS 105: 30I I-6).
- PD1 and like family members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail that is responsible for the binding of signaling molecules.
- the cytoplasmic tail of PD1 contains two tyrosine-based signaling motifs, an ITIM (immunoreceptor tyrosine-based inhibition motif) and an ITSM (immunoreceptor tyrosine-based switch motif).
- tumour infiltrating lymphocytes and/or PD-L1 (on tumour cells) has been found in a number of primary tumour biopsies assessed by immunohistochemistry.
- tissue include cancers of the lung, liver, ovary, cervix, skin, colon, glioma, bladder, breast, kidney, esophagus, stomach, oral squamous cell, urothelial cell, and pancreas as well as tumours of the head and neck (Brown, J. A., et al., (2003) J Immunol. I 70: I257-I266; Dong H., et al., (2002) Nat. Med.
- Antibody blockade effectively promoted tumour reactive CD8+ T cell infiltration into the tumour resulting in the up-regulation of anti-tumour effectors including IFN gamma, granzyme Band perforin. Additionally, the authors showed that PD1 blockade can be effectively combined with chemotherapy to yield a synergistic effect. In another study, using a model of squamous cell carcinoma in mice, antibody blockade of PD1 or PD-L1 significantly inhibited tumour growth (Tsushima, F., et al., (2006) Oral Oneal. 42: 268-274).
- PD1 antagonist means any chemical compound or biological molecule that stimulates an immune reaction through inhibition of PD1 signalling.
- 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%.
- Enhancement is achieved when the activity value relative to the control is about 110%, generally at least 120%, more generally at least 140%, more generally at least 160%, often at least 180%, more often at least 2-fold, most often at least 2.5-fold, usually at least 5-fold, more usually at least 10-fold, preferably at least 20-fold, more preferably at least 40- fold, and most preferably over 40-fold higher.
- PD1 The major function of PD1 is to limit the activity of T-cells at the time of an anti-inflammatory response to infection and to limit autoimmunity. PD1 expression is induced when T-cells become activated, and binding of one of its own ligands inhibits kinases involved in T-cell activation. Hence, in the tumour environment this may translate into a major immune resistance, because many tumours are highly infiltrated with TReg cells that further suppress effector immune responses. This resistance mechanism is partially alleviated by the use of PD1 inhibitors in combination with the ADC.
- PBDs are a class of naturally occurring anti-tumour 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 tumour 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 tumours as opposed to normal tissues.
- CTLA-4 is a receptor found on surface of activated T-cells and regulatory T-cells (Tregs).
- CTLA-4 mainly acts by competing with CD28 receptors for binding to B7 ligands (B7-1/CD80 and B7- 2/CD86) on antigen presenting cells (APCs).
- B7 ligands B7-1/CD80 and B7- 2/CD86
- APCs antigen presenting cells
- CD28 receptors on T-cells bind to B7 ligands on APCs and provide the essential second activation signal for T-cells.
- CTLA-4 receptors bind to B7 ligands with higher affinity and at a lower surface density and thereby outcompete CD28 receptors for binding with B7 ligands.
- CTLA-4 receptors also sequester B7- ligands from the surface of the APCs and result in significant depletion of the ligands on their surface.
- CTLA-4 interacts with B7 ligands to transduce a signal leading to inactivation of T cells bearing the CTLA-4 receptor. Disruption of this interaction effectively induces, enhances or prolongs the activation of such T cells, thereby inducing, enhancing or prolonging an immune response.
- CTLA-4 antagonist means any chemical compound or biological molecule that stimulates an immune reaction through inhibition of CTLA-4 signalling.
- 0X40 (CD134) is an activating receptor expressed by Treg cells, activated T cells and NK cells.
- 0X40 binds OX40L (CD252), which is expressed on numerous cell types including B cells, neutrophils, endothelial cells, mast cells dendritic cells and monocytes.
- the OX40-OX40L pathway can inhibit Treg function and activate CD8+ T cells.
- ⁇ C40 agonist means any chemical compound or biological molecule that stimulates an immune reaction through activation of 0X40 signalling.
- GITR is expressed in various T cell types, including T lymphocytes.
- the GITR-GITR ligand (GITRL) pathway can inhibit Treg function and activate CD8+ T cells.
- GITR agonist means any chemical compound or biological molecule that stimulates an immune reaction through activation of GITR signalling.
- LAG-3 is expressed on CD4 T cells, CD8 T cells and NK cells. LAG-3 interacts with MHC class II and LSECtin expressed on antigen-presenting cells, liver cells, and some tumour cells.
- LAG-3 antagonist means any chemical compound or biological molecule that stimulates an immune reaction through inhibition of LAG-3 signalling.
- TIM-3 is expressed on CD4 T cells, CD8 T cells, dendritic cells, natural killer cells, monocytes and macrophages.
- TIM-3 binds to ligands such as galectin-9, phosphatidyl esrine, high mobility group protein B1 , and Ceacam-1 expressed on endothelial cells, apoptotic cells, and some tumour cells.
- TIM-3 antagonist means any chemical compound or biological molecule that stimulates an immune reaction through inhibition of TIM-3 signalling.
- TIGIT is expressed on CD4 T cells, CD8 T cells and NK cells. TIGIT interacts with CD155 (PVR) and CD122 (PVRL2, nectin-2) expressed on antigen-presenting cells, T cells and some tumour cells.
- TIGIT antagonist means any chemical compound or biological molecule that stimulates an immune reaction through inhibition of TIGIT signalling.
- an anti-DLK-1-ADC such as ADCT-701 can be used to target and directly kill DLK1 (+) cancer cells.
- DLK-1 (+) tumour cells Next to DLK-1 (+) tumour cells, DLK-1 (-) tumour cells in close proximity to DLK-1 (+) tumour cells will potentially be killed by the bystander mechanism of the PBD-dimer released after cell kill of DLK-1 (+) cells. The resulting release of tumour associated antigens from cells that are killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use checkpoint modulators.
- ADCT-701 which targets DLK-1- positive tumours, with PD1 inhibitors is advantageous, because on the one hand, ADCT-701 will directly kill the DLK-1 -positive tumour cells, while on the other hand the PD1 inhibitor will engage the patient’s own immune system to eliminate the cancer cells.
- DLK-1 (+) tumour cells DLK-1 (-) tumour cells in close proximity to DLK-1 (+) tumour cells will potentially be killed by the bystander mechanism of the PBD-dimer released after cell kill of DLK-1 (+) cells.
- ADCT-701 will directly kill the tumour cells.
- tumour associated antigens from cells that are killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use of programmed cell death protein 1 (PD1) inhibitors, expressed on a large proportion of tumour infiltrating lymphocytes (TILs) from many different tumour types.
- PD1 programmed cell death protein 1
- Blockade of the PD1 pathway may enhance antitumour immune responses against the antigens released from the tumours killed by ADCT-701 by diminishing the number and/or suppressive activity of intratumoural TReg cells.
- the major function of PD1 is to limit the activity of T-cells at the time of an anti-inflammatory response to infection and to limit autoimmunity.
- PD1 expression is induced when T-cells become activated, and binding of one of its own ligands inhibits kinases involved in T-cell activation. Hence, in the tumour environment this may translate into a major immune resistance, because many tumours are highly infiltrated with TReg cells that probably further suppress effector immune responses. This resistance mechanism is alleviated by the use of PD1 inhibitors in combination with ADCT-701.
- ADCT-701 which targets DLK-1 -positive tumours, with PDL1 inhibitors is advantageous, because on the one hand, ADCT-701 will directly kill the DLK-1 -positive tumour cells, while on the other hand the PDL1 inhibitor will engage the patient’s own immune system to eliminate the cancer cells.
- DLK-1 (+) tumour cells target negative tumour cells in close proximity to DLK-1 (+) tumour cells will potentially be killed by the bystander mechanism of the PBD-dimer released after cell kill of DLK-1 (+) cells.
- ADCT-701 will directly kill the tumour cells.
- tumour associated antigens from cells that are killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use of programmed cell death protein 1 ligand inhibitors (PD-L1 , aka B7-H1 or CD274 ).
- PDL1 programmed cell death protein 1 ligand inhibitors
- PD-L1 programmed cell death protein 1 ligand inhibitors
- B7-H1 or CD274 programmed cell death protein 1 ligand inhibitors
- ADCT-701 which targets DLK1 positive lymphomas and leukemias, with CTLA4 inhibitors is advantageous, because on the one hand, ADCT-701 will directly kill the DLK1 positive tumour cells, while on the other hand the CTLA4 inhibitor will engage the patient’s own immune system to eliminate the cancer cells.
- DLK1 (+) tumour cells target negative tumour cells in close proximity to DLK1 (+) tumour cells will potentially be killed by the bystander mechanism of the PBD-dimer released after cell kill of DLK1(+) cells. Hence, ADCT-701 will directly kill the tumour.
- tumour associated antigens from cells killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use of CTLA4 inhibitors expressed on a large proportion of tumour infiltrating lymphocytes (TILs) from many different tumour types.
- CTLA4 (CD152) is to regulate the amplitude of the early stages of T cell activation, and as such it counteracts the activity of the T cell co-stimulatory receptor, CD28, In the tumour microenvironment.
- Blockade of the CTLA4 pathway may therefore enhance enhancement of effector CD4+T cell activity, while it inhibits Treg cell-dependent immunosuppression. Therefore it will be beneficial to target a DLK1 (+) tumour with ADCT-701 , causing the antigenic cell death, while the CTLA4 blockade induces a stronger immune, durable response.
- ADCT-701 which targets DLK1 positive lymphomas and leukemias, with 0X40 agonists is advantageous, because on the one hand ADCT-701 will directly kill the DLK1 positive tumour cells, while on the other hand the 0X40 agonist will engage the patient’s own immune system to eliminate the cancer cells.
- DLK1 (+) tumour cells target negative tumour cells in close proximity to DLK1 (+) tumour cells will potentially be killed by the bystander mechanism of the PBD- dimer released after cell kill of DLK1 (+) cells.
- ADCT-701 will directly kill the tumour.
- the resulting release of tumour associated antigens from cells killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use of a 0X40 agonist.
- 0X40 (CD134; TNFRSF4) is a member of the TNFR super-family and is expressed by CD4 and CD8 T cells during antigen-specific priming. 0X40 expression is largely transient following TCR/CD3 cross-linking, and by the presence of inflammatory cytokines. In the absence of activating signals, relatively few mature T cell subsets express 0X40 at biologically relevant levels. Generating optimal “killer” CD8 T cell responses requires T cell receptor activation plus co-stimulation, which can be provided through ligation of 0X40 using a 0X40 agonist. This activating mechanism augments T cell differentiation and cytolytic function leading to enhanced anti-tumour immunity. Therefore it will be beneficial to target a DLK1 (+) tumour with ADCT-701 , causing the antigenic cell death, while the 0X40 agonist induces a stronger, durable immune response.
- ADCT-701 which targets DLK1 positive lymphomas and leukemias, with GITR agonists is advantageous, because on the one hand ADCT-701 will directly kill the DLK1 positive tumour cells, while on the other hand the GITR agonist will engage the patient’s own immune system to eliminate the cancer cells.
- DLK1 (+) tumour cells target negative tumour cells in close proximity to DLK1 (+) tumour cells will potentially be killed by the bystander mechanism of the PBD- dimer released after cell kill of DLK1 (+) cells.
- ADCT-701 will directly kill the tumour.
- the resulting release of tumour associated antigens from cells killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use of a GITR agonist.
- GITR Glucocorticoid- induced tumour-necrosis-factor-receptor-related protein
- GITR ligation via its ligand GITRL stimulates both proliferation and function of both effector and regulatory CD4+ T cells. This promotes T-cell survival, and differentiation into effector cells, while abrogating suppression. Therefore it will be beneficial to target a DLK1 (+) tumour with ADCT-701 , causing the antigenic cell death, while the GITR agonist induces a stronger, durable immune response.
- DLK1 is also expressed on immune cells that infiltrate the local tumour environment and which can have a suppressive impact on the innate immune response against the tumour.
- immune cells that infiltrate the local tumour environment and which can have a suppressive impact on the innate immune response against the tumour.
- Examples are Tregs, NK cells, DC cells or macrophages.
- An anti-DLK-1-ADC such as ADCT-701 can be used to target these immune cells, which on the one hand will kill the immune suppressive cells, boosting the immune response. Also, killing of the immune cells by ADCT-701 will release local PBD warhead which is able to kill subsequent neighbouring cells via bystander kill.
- tumours not expressing DLK1 can be killed by targeting immune cells in the local tumour environment.
- target negative tumour cells killed by PBD released from neighbouring immune cells will induce immunogenic cell death further strengthening the anti-tumour immune response.
- ADCT-701 Combining ADCT-701 with PD1 inhibitors for treatment of DLK1 negative tumours is advantageous, because on the one hand, ADCT-701 will indirectly kill the DLK1 negative tumour cells via local bystander kill released from tumour infiltrating lymphocytes killed by ADCT-701 , while on the other hand the PD1 inhibitor will engage the patient’s own immune system to eliminate the cancer cells.
- the resulting release of tumour associated antigens from cells that are killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use of programmed cell death protein 1 (PD1) inhibitors, expressed on a large proportion of tumour infiltrating lymphocytes (TILs) from many different tumour types.
- PD1 inhibitors programmed cell death protein 1
- Blockade of the PD1 pathway may enhance antitumour immune responses against the antigens released from the tumours killed by ADCT-701 by diminishing the number and/or suppressive activity of intratumoural Treg cells.
- the major function of PD1 is to limit the activity of T-cells at the time of an anti-inflammatory response to infection and to limit autoimmunity. PD1 expression is induced when T-cells become activated, and binding of one of its own ligands inhibits kinases involved in T-cell activation. Hence, in the tumour environment this may translate into a major immune resistance, because many tumours are highly infiltrated with TReg cells that probably further suppress effector immune responses. This resistance mechanism is alleviated by the use of PD1 inhibitors in combination with ADCT-701 .
- ADCT-701 Combining ADCT-701 with PDL1 inhibitors for treatment of DLK1 negative tumours is advantageous, because on the one hand, ADCT-701 will indirectly kill the DLK1 negative tumour cells via local bystander kill released from tumour infiltrating lymphocytes killed by ADCT-701 , while on the other hand the PDL1 inhibitor will engage the patient’s own immune system to eliminate the cancer cells.
- the resulting release of tumour associated antigens from cells that are killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use of programmed cell death protein 1 ligand inhibitors (PD-L1 , aka B7-H1 or CD274 ).
- PDL1 is commonly upregulated on the tumour cell surface from many different human tumours.
- Interfering with the PD1 ligand expressed on the tumour will avoid the immune inhibition in the tumour microenvironment and therefore blockade of the PD1 pathway using PDL1 inhibitors may enhance antitumour immune responses against the antigens released from the tumours killed by ADCT-701 .
- Blockade of the PDL1 pathway may enhance antitumour immune responses against the antigens released from the tumours killed by ADCT-701 by diminishing the number and/or suppressive activity of intratumoural Treg cells.
- the major function of PD1 is to limit the activity of T-cells at the time of an anti-inflammatory response to infection and to limit autoimmunity. PD1 expression is induced when T-cells become activated, and binding of one of its own ligands inhibits kinases involved in T-cell activation. Hence, in the tumour environment this may translate into a major immune resistance, because many tumours are highly infiltrated with TReg cells that probably further suppress effector immune responses. This resistance mechanism is alleviated by the use of PD1 inhibitors in combination with ADCT-701.
- ADCT-701 Combining ADCT-701 with CTLA4 inhibitors for treatment of DLK1 negative tumours is advantageous, because on the one hand, ADCT-701 will indirectly kill the DLK1 negative tumour cells via local bystander kill released from tumour infiltrating lymphocytes killed by ADCT-701 , while on the other hand the CTLA4 antagonist will engage the patient’s own immune system to eliminate the cancer cells.
- the resulting release of tumour associated antigens from cells killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use of CTLA4 inhibitors expressed on a large proportion of tumour infiltrating lymphocytes (TILs) from many different tumour types.
- TILs tumour infiltrating lymphocytes
- CTLA4 The major function of CTLA4 (CD152) is to regulate the amplitude of the early stages of T cell activation, and as such it counteracts the activity of the T cell co-stimulatory receptor, CD28, In the tumour microenvironment. Blockade of the CTLA4 pathway may therefore enhance enhancement of effector CD4+T cell activity, while it inhibits TReg cell-dependent immunosuppression. Therefore it will be beneficial to target a DLK1 (+) tumour with ADCT-701 , causing the antigenic cell death, while the CTLA4 blockade induces a stronger immune, durable response.
- ADCT-701 Combining ADCT-701 with 0X40 agonists for treatment of DLK1 negative tumours is advantageous, because on the one hand, ADCT-701 will indirectly kill the DLK1 negative tumour cells via local bystander kill released from tumour infiltrating lymphocytes killed by ADCT-701 , while on the other hand the 0X40 agonist will engage the patient’s own immune system to eliminate the cancer cells. The resulting release of tumour associated antigens from cells killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use of a 0X40 agonist.
- 0X40 (CD134; TNFRSF4) is a member of the TNFR super-family and is expressed by CD4 and CD8 T cells during antigen-specific priming.
- 0X40 expression is largely transient following TCR/CD3 cross-linking, and by the presence of inflammatory cytokines. In the absence of activating signals, relatively few mature T cell subsets express 0X40 at biologically relevant levels. Generating optimal “killer” CD8 T cell responses requires T cell receptor activation plus co-stimulation, which can be provided through ligation of 0X40 using a 0X40 agonist. This activating mechanism augments T cell differentiation and cytolytic function leading to enhanced anti-tumour immunity. Therefore it will be beneficial to target a DLK1 (+) tumour with ADCT-701 , causing the antigenic cell death, while the 0X40 agonist induces a stronger, durable immune response.
- ADCT-701 Combining ADCT-701 with GITR agonists for treatment of DLK1 negative tumours is advantageous, because on the one hand, ADCT-701 will indirectly kill the DLK1 negative tumour cells via local bystander kill released from tumour infiltrating lymphocytes killed by ADCT-701 , while on the other hand the GITR agonist will engage the patient’s own immune system to eliminate the cancer cells. The resulting release of tumour associated antigens from cells killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use of a GITR agonist.
- GITR Glucocorticoid-induced tumour-necrosis-factor-receptor-related protein
- GITR ligation via its ligand GITRL stimulates both proliferation and function of both effector and regulatory CD4+ T cells. This promotes T-cell survival, and differentiation into effector cells, while abrogating suppression. Therefore it will be beneficial to target a DLK1 (+) tumour with ADCT-701 , causing the antigenic cell death, while the GITR agonist induces a stronger, durable immune response.
- a panel of solid tumour-derived cell lines will be treated with a range of concentration of each ADC and a checkpoint modulator. 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.
- samples or assays comprising a given, e.g., protein, gene, cell, or organism, are treated with a potential 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%.
- samples or assays comprising a given, e.g., protein, gene, cell, or organism, are treated with a potential activating agent and are compared to control samples treated with an inactive control molecule.
- Control samples are assigned a relative activity value of 100%. Activation is achieved when the activity value relative to the control is about 110%, generally at least 120%, more generally at least 140%, more generally at least 160%, often at least 180%, more often at least 2-fold, most often at least 2.5- fold, usually at least 5-fold, more usually at least 10-fold, preferably at least 20-fold, more preferably at least 40-fold, and most preferably over 40-fold higher.
- checkpoint modulators suitable for use in the present disclosure include:
- PD-1 antagonists PD-L1 antagonists, CTLA-4 antagonists, 0X40 agonists, and GITR agonists are particularly preferred checkpoint modulators for use in the methods of the present disclosure.
- Nivolumab, Pembrolizumab, Cemiplimab, Atezolizumab, Durvalumab, Avelumab and Ipilimumab are particularly preferred checkpoint modulators for use in the methods of the present disclosure.
- Pembrolizumab is a particularly preferred checkpoint modulator for use in the methods of the present disclosure.
- PD1 polypeptide corresponds to Genbank accession no. AAC51773, version no. AAC51773.1 , record update date: Jun 23, 2010 09:24 AM.
- the nucleic acid encoding PD1 polypeptide corresponds to Genbank accession no. U64863, version no. U64863.1 , record update date: Jun 23, 2010 09:24 AM.
- PD1 polypeptide corresponds to Uniprot/Swiss-Prot accession No. Q15116.
- PDL1 polypeptide corresponds to Genbank accession no. AAI13735, version no. AAI13735.1.
- the nucleic acid encoding PDL1 polypeptide corresponds to Genbank accession no. BC113734, version no. BC113734.1.
- PDL1 polypeptide corresponds to Uniprot/Swiss-Prot accession No. Q9NZQ7.
- CTLA-4 polypeptide corresponds to Genbank accession no. AAD00698, version no. AAD00698.1.
- the nucleic acid encoding CTLA-4 polypeptide corresponds to Genbank accession no. U90273, version no. U90273.1.
- CTLA-4 polypeptide corresponds to Uniprot/Swiss-Prot accession No. P16410.
- the secondary agent selected from gemcitabine.
- a PARP inhibitor and a checkpoint modulator when used as a single agent in isolation has demonstrated clinical utility - for example in the treatment of cancer.
- the efficacy of an anti-DLK1 ADC in the treatment of, for example, cancer has been established - see, for example, WO2018/146199. Based on their work with numerous PBD- ADCs, the present authors believe that an anti-DLK1 ADC, such as ADCT-701 , would demonstrate clinical utility, for example in the treatment of cancer, when used as a single agent in isolation.
- combination of the anti-DLK1 ADC and a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator is expected to provide one or more of the following advantages over treatment with either anti-DLK1 ADC or the secondary agent alone:
- Effective treatment of a broader range of cancers as used herein means that following treatment with the combination a complete or partial response is observed with a greater range of recognised cancer types. That is, a complete or partial response is seen from cancer types not previously reported to completely respond to either anti-DLK1 ADC or the secondary agent alone.
- Effective treatment of a resistant, refractory, or relapsed forms as used herein means that following treatment with the combination a complete or partial response is observed in individuals that are either partially or completely resistant or refractory to treatment with either anti-DLK1 ADC or the secondary agent 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 or partial response following treatment with the anti-DLK1 ADC / secondary agent combination is observed in at least 10%, 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-DLK1 ADC or the secondary agent alone.
- Increased response rate to treatment means that following treatment with the combination a complete or partial response is observed in a greater proportion of individuals than is observed following treatment with either anti-DLK1 ADC or the secondary agent.
- 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.
- partial response is used herein to mean a reduction in any clinical evidence of disease in an individual.
- a partial response may mean a reduction in the size of a tumour, in the expression of tumour markers, or in the extent of cancer in the body.
- Evidence may be assessed using the appropriate methodology in the art, for example CT or PET scanning, or biopsy where appropriate.
- a partial response may mean at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% decrease in the diameter of a tumour.
- the number of doses required to achieve partial response may be one, two, three, four, five, ten or more.
- the individuals achieve partial 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 tumour tissue whereby greater selectivity, i.e. a lower efficacious dose, may be achieved.
- the present disclosure provides combined therapies comprising administering an anti-DLK1 ADC which binds DLK1 for use in therapy, wherein the method comprises selecting a subject based on expression of the target protein.
- 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.
- 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 carcinoma, 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.
- neoplasms and tumours e.g. histocytoma, glioma, astrocyoma, osteoma
- cancers e.g. lung cancer, small cell
- 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 to be treated herein include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
- Cancers of particular interest include: squamous cell cancer (e.g.
- epithelial squamous cell cancer epithelial squamous cell cancer
- hepatocellular carcinoma hepatoblastoma
- lung cancer non small cell lung cancer, small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, breast cancer, ovarian cancer, gastric cancer, stomach cancer, gastrointestinal cancer, bowel cancer, colon cancer, rectal cancer, colorectal cancer, anal carcinoma, breast carcinoma, ovarian carcinoma, cervical cancer, endometrial or uterine carcinoma, vulval cancer, prostate cancer, testicular cancer, penile carcinoma, cancer of the peritoneum, liver cancer, cholangiacarcinoma, hepatocellular cancer, hepatocellular carcinoma, hepatoma, hepatic carcinoma, rhabdomyosarcoma, cholangiacarcinoma, kidney cancer, renal cancer, bladder cancer, pancreatic cancer, head and neck cancer, brain cancer, sarcoma, osteosarcoma
- Cancers of particular interest include myelodysplastic syndrome, acute myeloid leukaemia, hepatoblastoma, small cell lung cancer, colon cancer, neuroblastoma, adrenal gland cancer, pheochromocytoma, paraganglioma and skeletal muscle tumour.
- Cancers of particular interest include small cell lung cancer, neuroblastoma, adrenal gland cancer, pheochromocytoma and paraganglioma.
- disorders of interest include any condition in which DLK1 is overexpressed, or wherein DLK1 antagonism will provide a clinical benefit.
- DLK1 antagonism will provide a clinical benefit.
- diseases include immune disorders, cardiovascular disorders, thrombosis, diabetes, immune checkpoint disorders, fibrotic disorders (fibrosis), or proliferative diseases such as cancer, particularly metastatic cancer.
- 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.
- the proliferative disease may be characterised by the presence of a neoplasm comprising DLK1+ve cells.
- the proliferative disease may be characterised by the presence of a neoplasm comprising both DLK1+ve and DLK1-ve cells.
- the proliferative disease may be characterised by the presence of DLK1+ve non-neoplastic cells, for instance DLK1+ve tumour-associated non-tumour cells.
- the target neoplasm or neoplastic cells may be all or part of a solid tumour, such as an advanced solid tumour.
- Solid tumours may be neoplasms, including non-haematological cancers, comprising or composed of DLK1+ve neoplastic cells.
- Solid tumours may be neoplasms, including non-haematological cancers, comprising or composed of DLK1+ve neoplastic cells and DLK1-ve neoplastic cells.
- the solid tumour may be associated with DLK1+ve infiltrating cells.
- Solid tumours may be neoplasms, including non-haematological cancers, infiltrated with DLK1+ve cells.
- the antibody-drug conjugates (ADC) of the present invention may be used to treat various diseases or disorders, e.g. characterized by the overexpression of a tumour antigen.
- exemplary conditions or hyperproliferative disorders include benign or malignant tumours; leukemia, haematological, and lymphoid malignancies.
- Others include neuronal, glial, astrocytal, hypothalamic, glandular, macrophagal, epithelial, stromal, blastocoelic, inflammatory, angiogenic and immunologic, including autoimmune, disorders.
- Autoimmune diseases for which the ADC compounds may be used in treatment include rheumatologic disorders (such as, for example, rheumatoid arthritis, Sjogren's syndrome, scleroderma, lupus such as SLE and lupus nephritis, polymyositis/dermatomyositis, cryoglobulinemia, anti-phospholipid antibody syndrome, and psoriatic arthritis), osteoarthritis, autoimmune gastrointestinal and liver disorders (such as, for example, inflammatory bowel diseases (e.g.
- autoimmune gastritis and pernicious anemia autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and celiac disease
- vasculitis such as, for example, ANCA-associated vasculitis, including Churg-Strauss vasculitis, Wegener's granulomatosis, and polyarteriitis
- autoimmune neurological disorders such as, for example, multiple sclerosis, opsoclonus myoclonus syndrome, myasthenia gravis, neuromyelitis optica, Parkinson’s disease, Alzheimer’s disease, and autoimmune polyneuropathies
- renal disorders such as, for example, glomerulonephritis, Goodpasture’s syndrome, and Berger’s disease
- autoimmune dermatologic disorders such as, for example, psoriasis, urticaria, hives, pemphigus vulgaris, bullous pemphigoid,
- Graves’ disease and thyroiditis More preferred such diseases include, for example, rheumatoid arthritis, ulcerative colitis, ANCA- associated vasculitis, lupus, multiple sclerosis, Sjogren's syndrome, Graves’ disease, IDDM, pernicious anemia, thyroiditis, and glomerulonephritis.
- 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, small cell lung cancer, neuroblastoma, adrenal gland cancer, pheochromocytoma or paraganglioma.
- individuals may have, or be suspected of having, or be at risk of having, a solid cancer that has tumour associated non-tumour cells that express DLK1 , such as infiltrating cells that express DLK1.
- subjects are selected on the basis of the amount or pattern of expression of DLK1 .
- the selection is based on expression of DLK1 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 DLK1 .
- the neoplasm may be composed of cells having surface expression of DLK1.
- subjects are selected on the basis they have a neoplasm comprising DLK1+ve cells.
- the neoplasm may comprise both DLK1+ve and DLK1-ve cells.
- the neoplasm may comprise DLK1+ve non-neoplastic cells.
- the neoplasm or neoplastic cells may be all or part of a solid tumour, such as an advanced solid tumour.
- the solid tumour may be infiltrated with DLK1+ve cells.
- expression of DLK1 in a particular tissue of interest is determined. For example, in a sample of tumour tissue.
- systemic expression of DLK1 is determined.
- 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 DLK1 expression in a sample. In those cases, subjects without DLK1 expression may be considered not suitable for treatment.
- the level of DLK1 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 DLK1 as determined by immunohistochemistry (IHC).
- IHC immunohistochemistry
- 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 DLK1. 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 DLK1 .
- the presence of DLK1 in cells in the sample indicates that the individual is suitable for treatment with a combination comprising an anti-DLK1 ADC and the secondary agent.
- the amount and/or expression of DLK1 must be above a threshold level to indicate that the individual is suitable for treatment.
- the observation that DLK1 expression 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 DLK1 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 DLK1. 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 DLK1.
- 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-DLK1 ADC if the individual has been treated with the secondary agent. In some embodiments the individual is selected for treatment with the anti-DLK1 ADC if the individual is being treated with the secondary agent. In some cases the individual is selected for treatment if they are refractory to treatment (or further treatment) with the secondary agent. In embodiments where the individual is undergoing, or has undergone, treatment with the secondary agent, the anti-DLK1 ADC may be administered in combination with the secondary agent, or without continued administration of the secondary agent.
- the anti-DLK1 ADC is administered to the selected individual in combination with the secondary agent. In some embodiments the anti-DLK1 ADC is administered to the selected individual without continued administration of the secondary agent.
- the term ‘refractory to treatment (or further treatment) with the secondary agent’ is used herein to mean that the disorder (such as cancer) does not respond, or has ceased to respond, to administration of the secondary agent when administered as a monotherapy.
- 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 tumour tissue, such as cancerous tumour tissue.
- the sample may have been obtained by a tumour 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. Accordingly, the sample may be a blood sample or lymph sample. In some cases, 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 DLK1 .
- the individual may be an animal, such as a mammal, including 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.
- 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 DLK1+ve cells.
- the proliferative disease may be characterised by the presence of a neoplasm comprising DLK1+ve cells.
- the proliferative disease may be characterised by the presence of a neoplasm comprising both DLK1+ve and DLK1-ve cells.
- the proliferative disease may be characterised by the presence of DLK1+ve non-neoplastic cells, for instance DLK1+ve tumour-associated non-tumour cells.
- the individual has received a diagnosis of a solid tumour containing DLK1+ve infiltrating cells, such as an advanced solid tumour containing DLK1+ve infiltrating cells.
- Solid tumours may be neoplasms, including non-haematological cancers, comprising or composed of DLK1+ve neoplastic cells.
- Solid tumours may be neoplasms, including non-haematological cancers, infiltrated with DLK1+ve cells.
- Solid tumours may be infiltrated with DLK1+ve nonneoplastic cells, for instance DLK1+ve tumour-associated non-tumour 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-701.
- the cancer is ovarian, breast, prostate or renal cancer.
- the cancer is small cell lung cancer, neuroblastoma, adrenocortical carcinoma, pheochromocytoma and paraganglioma.
- the individual may be undergoing, or have undergone, treatment with the secondary agent. In some cases the individual may be refractory to treatment (or further treatment) with the secondary agent. In embodiments where the individual is undergoing, or has undergone, treatment with the secondary agent, the anti-DLK1 ADC may be administered in combination with the secondary agent, or without continued administration of the secondary agent.
- 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.
- the “therapeutically-effective amount” or “effective amount” of the anti-DLK1 ADC and/or the secondary agent used in the combination therapy may correspond to an amount of the anti-DLK1 ADC or the secondary agent which would be considered sub-optimal when used in monotherapy. Without wishing to be bound by theory, the authors believe this is due to a synergistic interaction between the anti-DLK1 ADC and the secondary agent.
- 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.
- the “prophylactically -effective amount” or “effective amount” of the anti-DLK1 ADC and/or the secondary agent used in the combination therapy may correspond to an amount of the anti-DLK1 ADC or the secondary agent which would be considered sub-optimal when used in monotherapy. Without wishing to be bound by theory, the authors believe this is due to a synergistic interaction between the anti-DLK1 ADC and the secondary agent.
- a method of treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of an anti-DLK1 ADC and a secondary agent selected from gemcitabine, a PARP inhibitor and a checkpoint modulator.
- a 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 time-course 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-DLK1 ADC comprises an anti-DLK1 antibody.
- the anti-DLK1 antibody may be HuBa-1-3d as disclosed herein.
- the ADC may comprise a drug which is a PBD dimer.
- the anti-DLK1 ADC may be as defined in the section herein entitled “Anti-DLK1 ADCs”.
- the ADC may be an anti-DLK1 ADC such as ADCT-701 .
- the ADC may be an ADC disclosed in WO2018/146199.
- the treatment may involve administration of the anti-DLK1 ADC / secondary agent 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:
- 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/antitumour antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors.
- Chemotherapeutic agents include compounds used in “targeted therapy” and conventional chemotherapy.
- 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-DLK1 ADC and/or the secondary agent, 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-DLK1 ADC is determined by the expression of DLK1 observed in a sample obtained from the subject.
- the level or localisation of expression of DLK1 in the sample may be indicative that a higher or lower dose of anti-DLK1 ADC is required.
- a high expression level of DLK1 may indicate that a higher dose of anti-DLK1 ADC would be suitable.
- a high expression level of DLK1 may indicate the need for administration of another agent in addition to the anti-DLK1 ADC.
- a high expression level of DLK1 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.
- 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 DLK1 .
- Antibodies may be murine, human, humanized, chimeric, or derived from other species such as rabbit, goat, sheep, horse or camel.
- An 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 , G1 m2, G1 m3, non-G1 m1 [that, is any allotype other than G1 m1], 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-id) 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 et al (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 nonhuman primate (e.g. Old World Monkey or Ape) and human constant region sequences.
- the antibodies herein may be modified (or further modified) as described in, for example, WO2018/146199.
- Example 1 Prophetic in vitro study of ADCT-701 and Gemcitabine
- ADCT-701 is an anti-DLK1 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, Zammarchi et al. AACR Annual Meeting 2018, April 14-18, Chicago, lllionis, and as described herein).
- ADC anti-DLK1 antibody-drug conjugate
- ADCT-701 and gemcitabine In vitro, the combination of ADCT-701 and gemcitabine will be evaluated in DLK1 -expressing cancer cell lines. Increasing concentration of ADCT-701 and gemcitabine will be tested either as single agents or in combination. After an incubation period of the test items with the cells of 3-7 days, the combination index will be calculated according to the Chou-Talalay method. Analysis of the median combination index values will be used to determine if the combination of ADCT-701 and gemcitabine has synergistic/additive/non beneficial activity.
- ADCT-701 can be administered either concomitantly with gemcitabine or after a certain time interval after gemcitabine dosing has started.
- ADCT-701 is dosed as a single dose between 0.1 and 1 mg/kg, while gemcitabine is dosed q3dx4 or q7dx4 at doses between 10 and 240 mg/kg.
- Tumour volumes and body weights of the mice will be measured for at least 30 days.
- the anti-tumour activity of the single agents and of the combination of the two agents will be assessed by determining tumour volumes over study duration, number of responders (partial responder, complete responder and tumour-free survivor) and survival benefit (log-rank test) at the end of the study.
- the coefficient of drug interaction (CDI) which will be calculated when at least 50% of the mice will be present in each group, will determine if the combination of the 2 drugs has synergistic/additive/non beneficial anti-tumour activity.
- ADCT-701 is an anti-DLK1 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, Zammarchi et al. AACR Annual Meeting 2018, April 14-18, Chicago, lllionis, and as described herein).
- ADC anti-DLK1 antibody-drug conjugate
- ADCT-701 and Olaparib In vitro, the combination of ADCT-701 and Olaparib will be evaluated in DLK1 -expressing cancer cell lines (either BRCA1/2 wild-type or mutated). Increasing concentration of ADCT-701 and Olaparib will be tested either as single agents or in combination. After an incubation period of the test items with the cells of 3-7 days, the combination index will be calculated according to the Chou- Talalay method. Analysis of the median combination index values will be used to determine if the combination of ADCT-701 and Olaparib has synergistic/additive/non beneficial activity.
- the purpose of this proposed study is to assess the in vivo efficacy of combination therapies in which an anti-DLK1 ADC is administered in combination with a PARP inhibitor.
- ADCT-701 and Olaparib will be tested in mice implanted with DLK-1- expressing tumour cells (either BRCA1/2 wild-type or mutated). Once the tumours will have reached a mean tumour volume of 100-300 mm 3 , ADCT-701 and Olaparib will be administered either as single agents or in combination. Typically, ADCT-701 is dosed as a single dose between 0.1 and 1 mg/kg, while olaparib is dosed daily for 2-5 weeks at doses between 10 and 100 mg/kg. Tumour volumes and body weights of the mice will be measured for at least 30 days.
- the anti-tumour activity of the single agents and of the combination of the two agents will be assessed by determining tumour volumes over study duration, number of responders (partial responder, complete responder and tumour-free survivor) and survival benefit (log-rank test) at the end of the study.
- the coefficient of drug interaction (CDI) which will be calculated when at least 50% of the mice will be present in each group, will determine if the combination of the 2 drugs has synergistic/additive/non beneficial anti-tumour activity.
- Example 5 Prophetic in vivo study of a PBD-based ADC against DLK1-701 and checkpoint modulator
- a PBD-based ADC against DLK1 combined with a checkpoint modulator shows additive or synergistic effect
- the combination is tested in vivo in a syngeneic tumour model in immunocompetent mice.
- an antibody cross reactive with mouse DLK-1 is site- specifically conjugated using GlycoConnectTM technology to PL1601 , which contains HydraSpaceTM, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is coadministered with the checkpoint modulator to mice grafted with a mouse tumour cell line expressing DLK-1.
- syngeneic models using mouse cell lines genetically engineered to express human DLK1 are used, for treatment with ADCT-701 .
- the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the checkpoint modulator is dosed Q3d x 3 at doses between 1 and 10 mg/kg.
- Control groups include the ADC or checkpoint modulator alone. Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group.
- Statistical analysis typically a log-rank test
- Example 5.2 tumours not expressing DLK1
- an antibody cross reactive with mouse DLK-1 is site-specifically conjugated using GlycoConnectTM technology to PL1601 , which contains HydraSpaceTM, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is co-administered with the checkpoint modulator to mice grafted with a mouse tumour cell line know to have high levels of infiltrating lymphocytes, such as but not limited to MC38 and CT26.
- the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the checkpoint modulator is dosed Q3d x 3 at doses between 1 and 10 mg/kg.
- Control groups include the ADC or checkpoint modulator alone.
- Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group.
- Statistical analysis typically a log-rank test is performed to determine whether the mice treated with the combination have outperformed the mice treated with either ADC or checkpoint modulator alone.
- Example 6 Prophetic in vivo study of a PBD-based ADC against DLK1 and a PD1 antagonist
- a PBD-based ADC against DLK1 combined with a PD1 inhibitor shows additive or synergistic effect
- the combination is tested in vivo in a syngeneic tumour model in immunocompetent mice.
- an antibody cross reactive with mouse DLK-1 is site- specifically conjugated using GlycoConnectTM technology to PL1601 , which contains HydraSpaceTM, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is coadministered with the PD1 inhibitor to mice grafted with a mouse tumour cell line expressing DLK-1.
- syngeneic models using mouse cell lines genetically engineered to express human DLK1 are used, for treatment with ADCT-701.
- the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the PD1 inhibitor is dosed Q3d x 3 at doses between 1 and 10 mg/kg.
- Control groups include the ADC or PD1 inhibitor alone. Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group.
- Statistical analysis typically a log-rank test
- Example 6.2 tumours not expressing DLK1
- an antibody cross reactive with mouse DLK-1 is site-specifically conjugated using GlycoConnectTM technology to PL1601 , which contains HydraSpaceTM, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is co-administered with the PD1 inhibitor to mice grafted with a mouse tumour cell line know to have high levels of infiltrating lymphocytes, such as but not limited to MC38 and CT26.
- the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the PD1 inhibitor is dosed Q3d x 3 at doses between 1 and 10 mg/kg.
- Control groups include the ADC or PD1 inhibitor alone.
- Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group.
- Statistical analysis typically a log-rank test is performed to determine whether the mice treated with the combination have outperformed the mice treated with either ADC or PD1 inhibitor alone.
- Example 7 Prophetic in vivo study of a PBD-based ADC against DLK1 and a PD-L1 antagonist
- a PBD-based ADC against DLK1 combined with a PDL1 inhibitor shows additive or synergistic effect
- the combination is tested in vivo in a syngeneic tumour model in immunocompetent mice.
- an antibody cross reactive with mouse DLK-1 is site- specifically conjugated using GlycoConnectTM technology to PL1601 , which contains HydraSpaceTM, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is coadministered with the PDL1 inhibitor to mice grafted with a mouse tumour cell line expressing DLK1 .
- syngeneic models using mouse cell lines genetically engineered to express human DLK1 are used, for treatment with ADCT-701.
- the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the PD1 inhibitor is dosed Q3d x 3 at doses between 1 and 10 mg/kg.
- Control groups include the ADC or PDL1 inhibitor alone. Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS mice is determined in each group.
- Statistical analysis typically a log-rank test
- Example 7.2 tumours not expressing DLK1
- an antibody cross reactive with mouse DLK-1 is site-specifically conjugated using GlycoConnectTM technology to PL1601 , which contains HydraSpaceTM, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is co-administered with the PDL1 inhibitor to mice grafted with a mouse tumour cell line know to have high levels of infiltrating lymphocytes, such as but not limited to MC38 and CT26.
- the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the PDL1 inhibitor is dosed Q3d x 3 at doses between 1 and 10 mg/kg.
- Control groups include the ADC or PDL1 inhibitor alone.
- Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group.
- Statistical analysis typically a log-rank test is performed to determine whether the mice treated with the combination have outperformed the mice treated with either ADC or PDL1 inhibitor alone.
- Example 8 Prophetic in vivo study of a PBD-based ADC against DLK1 and a CTLA4 antagonist
- a PBD-based ADC against DLK1 combined with a CTLA4 inhibitor shows additive or synergistic effect
- the combination is tested in vivo in a syngeneic tumour model in immunocompetent mice.
- an antibody cross reactive with mouse DLK-1 is site- specifically conjugated using GlycoConnectTM technology to PL1601 , which contains HydraSpaceTM, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is coadministered with the CTLA4 inhibitor to mice grafted with a mouse tumour cell line expressing DLK1.
- syngeneic models using mouse cell lines genetically engineered to express human DLK1 are used, for treatment with ADCT-701 .
- the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the CLTA4 inhibitor is dosed Q3d x 3 at doses between 1 and 10 mg/kg.
- Control groups include the ADC or CTLA4 inhibitor alone. Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group.
- Statistical analysis typically a log-rank test
- an antibody cross reactive with mouse DLK-1 is site-specifically conjugated using GlycoConnectTM technology to PL1601 , which contains HydraSpaceTM, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is co-administered with the CTLA4 antagonist to mice grafted with a mouse tumour cell line know to have high levels of infiltrating lymphocytes, such as but not limited to MC38 and CT26.
- the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the CTLA4 antagonist is dosed Q3d x 3 at doses between 1 and 10 mg/kg.
- Control groups include the ADC or CTLA4 antagonist alone.
- Example 9.1 tumours expressing DLK1
- a PBD-based ADC against DLK1 combined with a 0X40 agonist shows additive or synergistic effect
- the combination is tested in vivo in a syngeneic tumour model in immunocompetent mice.
- an antibody cross reactive with mouse DLK-1 is site- specifically conjugated using GlycoConnectTM technology to PL1601 , which contains HydraSpaceTM, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is coadministered with the 0X40 agonist to mice grafted with a mouse tumour cell line expressing DLK1 .
- syngeneic models using mouse cell lines genetically engineered to express human DLK1 are used, for treatment with ADCT-701.
- the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the 0X40 agonist is dosed Q3d x 3 at doses between 1 and 10 mg/kg.
- Control groups include the ADC or 0X40 agonist alone. Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group.
- Statistical analysis typically a log-rank test
- an antibody cross reactive with mouse DLK-1 is site-specifically conjugated using GlycoConnectTM technology to PL1601 , which contains HydraSpaceTM, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is co-administered with the 0X40 agonist to mice grafted with a mouse tumour cell line know to have high levels of infiltrating lymphocytes, such as but not limited to MC38 and CT26.
- the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the 0X40 agonist is dosed Q3d x 3 at doses between 1 and 10 mg/kg.
- Control groups include the ADC or 0X40 agonist alone. Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group. Statistical analysis (typically a log-rank test) is performed to determine whether the mice treated with the combination have outperformed the mice treated with either ADC or 0X40 agonist alone.
- Example 10 Prophetic in vivo study of a PBD-based ADC against DLK1 and a GITR agonist
- a PBD-based ADC against DLK1 combined with a GITR agonist shows additive or synergistic effect
- the combination is tested in vivo in a syngeneic tumour model in immunocompetent mice.
- an antibody cross reactive with mouse DLK-1 is site- specifically conjugated using GlycoConnectTM technology to PL1601 , which contains HydraSpaceTM, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is coadministered with the GITR agonist to mice grafted with a mouse tumour cell line expressing DLK1 .
- syngeneic models using mouse cell lines genetically engineered to express human DLK1 are used, for treatment with ADCT-701.
- the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the GITR agonist is dosed Q3d x 3 at doses between 1 and 10 mg/kg.
- Control groups include the ADC or GITR agonist alone. Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group.
- Statistical analysis typically a log-rank test
- Example 10.2 tumours not expressing DLK1
- an antibody cross reactive with mouse DLK-1 is site-specifically conjugated using GlycoConnectTM technology to PL1601 , which contains HydraSpaceTM, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is co-administered with the GITR agonist to mice grafted with a mouse tumour cell line know to have high levels of infiltrating lymphocytes, such as but not limited to MC38 and CT26.
- the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the GITR agonist is dosed Q3d x 3 at doses between 1 and 10 mg/kg.
- Control groups include the ADC or GITR agonist alone. Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group. Statistical analysis (typically a log-rank test) is performed to determine whether the mice treated with the combination have outperformed the mice treated with either ADC or GITR agonist alone.
Abstract
The present disclosure relates to combination therapy with a combination of ADCT-701 and a secondary agent selected from gemcitabine, a PARP inhibitor and a checkpoint modulator.
Description
COMBINATION THERAPY
Earlier applications
This application claims priority from United Kingdom application numbers GB2107713.6, filed 28 May 2021 ; GB2107706.0, filed 28 May 2021 ; and GB2107709.4, filed 28 May 2021. The priority applications are hereby incorporated by reference in their 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-DLK1 Antibody Drug Conjugate (anti-DLK1 ADC) and a secondary agent selected from gemcitabine. a PARP inhibitor and a checkpoint modulator.
BACKGROUND
Antibody therapy has been established for the targeted treatment of subjects with cancer, immunological and angiogenic disorders.
Delta-like 1 homolog protein (DLK1) is an EGF-like membrane bound protein consisting of six tandem EGF-like repeats, a juxtamembrane region with a TACE (ADAM17)-mediated cleavage site, a transmembrane domain, and a short intracellular tail. DLK1 is strongly expressed during fetal development, but its expression is turned down and highly restricted in adults. Conversely, DLK1 gets re-expressed in several tumours, such as neuroblastoma, hepatocellular carcinoma (HCC), rhabdomyosarcoma, small cell lung cancer, myelodysplastic syndrome and acute myeloid leukemia. Interestingly, in HCC DLK1 has been shown to be a marker of cancer stem cells, a subpopulation of cells responsible for tumour initiation, growth, metastasis, and recurrence. DLK1 represents an attractive target for an antibody-drug conjugate (ADC) approach based on its selective expression in a wide range of malignancies and restricted expression in healthy organs, as well as its expression on HCC cancer stem cells.
The efficacy of an Antibody Drug Conjugate comprising an anti-DLK1 antibody (an anti-DLK1 ADC) in the treatment of, for example, cancer has been established - see, for example, WO2018/146199. Research continues to further improve the efficacy, tolerability, and clinical utility of anti-DLK1 ADCs. To this end, the present authors have considered clinically advantageous combination therapies in which an anti-DLK1 ADC is administered in combination with gemcitabine.
SUMMARY
Based on their work with numerous PBD-ADCs, the present authors believe that the administration of a combination of an anti-DLK1 ADC and a secondary agent selected from gemcitabine. a PARP inhibitor and a checkpoint modulator to an individual leads to unexpected clinical advantages. The present authors further believe that administration of an anti-DLK1 ADC to an individual that has either been treated with, or is being treated with, gemcitabine leads to a synergistic increase in treatment efficacy.
Accordingly, in a first aspect the present disclosure provides a method for treating a disorder in an individual, the method comprising administering to the individual an anti-DLK1 ADC and a
secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator. In some cases, the method comprises administering an effective amount of an anti-DLK1 ADC and a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator. The method of treatment may further comprise selecting an individual for treatment. The individual may be selected for treatment with an anti-DLK1 ADC if he/she has been treated with a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator, if he/she is being treated with a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator, and/or if he/she is refractory to treatment, or further treatment, with a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator.
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 anti-DLK1 ADC. In some cases, the method comprises administering an effective amount of the anti-DLK1 ADC. The method of treatment may further comprise administering a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator in combination with the anti-DLK1 ADC.
In the disclosed methods, the treatment may comprise administering the anti-DLK1 ADC before the secondary agent, simultaneous with the secondary agent, or after the secondary agent. The disclosed methods may comprise administering a further chemotherapeutic agent to the individual. In the disclosed methods, the individual may be human.
In the disclosed methods, the individual may have a disorder or may have been determined to have a disorder. The individual may have cancer or may have been determined to have cancer. The individual may have, or have been determined to have, a cancer which expresses DLK1 . The cancer may comprise both DLK1+ve and DLK1-ve cancer cells. The individual may have, or have been determined to have, DLK1+ve tumour-associated non-tumour cells, such as DLK1+ve infiltrating cells.
In the disclosed methods, the individual may be undergoing treatment with the secondary agent and/or have previously undergone treatment with the secondary agent. The individual may be refractory to treatment, or further treatment, with the secondary agent.
In the disclosed methods, the neoplasm may be all or part of a solid tumour. The neoplasm may be all or part of an advanced solid tumour. Solid tumours may be neoplasms, including non- haematological cancers, comprising or composed of DLK1+ve neoplastic cells. Solid tumours may be neoplasms, including non-haematological cancers, comprising or composed of DLK1+ve neoplastic cells and DLK1-ve neoplastic cells. The solid tumour may be associated with DLK1+ve infiltrating cells. Solid tumours may be neoplasms, including non-haematological cancers, infiltrated with DLK1+ve cells.
In the disclosed methods, the disorder may be a proliferative disease, for example a cancer. The disorder may be a cancer such as hepatocellular carcinoma, hepatoblastoma, lung cancer, non small cell lung cancer, small cell lung cancer, breast cancer, gastric cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carcinoma, ovarian cancer, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, hepatocellular carcinoma, rhabdomyosarcoma, cholangiacarcinoma, kidney cancer, renal cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi’s sarcoma, melanoma, neuroblastoma, adrenal gland cancer, adrenocortical
carcinoma, pheochromocytoma, paraganglioma, thyroid medullary cancer, thyroid medullary carcinoma, skeletal muscle cancer, liposarcoma, bone-derived cancer glioma, Wilms tumour, neuroendocrine tumours, Acute Myeloid Leukemia or Myelodysplastic syndrome. Cancers of particular interest include myelodysplastic syndrome, acute myeloid leukaemia, hepatoblastoma, small cell lung cancer, colon cancer, neuroblastoma, adrenal gland cancer, pheochromocytoma, paraganglioma and skeletal muscle tumour. More specifically, cancers of particular interest include small cell lung cancer, neuroblastoma, adrenocortical carcinoma, pheochromocytoma and paraganglioma.
In the disclosed methods, the anti-DLK1 ADC may be as defined in the section herein entitled “Anti- DLK1 ADCs”. The anti-DLK1 ADC may be ADCT-701 .
In one aspect, the present disclosure provides an anti-DLK1 ADC, or a composition comprising an anti-DLK1 ADC, for use in a method of treatment as described herein. The anti-DLK1 ADC may be as defined in the section herein entitled “Anti-DLK1 ADCs”. The anti-DLK1 ADC may be ADCT-701 .
In one aspect, the present disclosure provides gemcitabine, or a composition comprising a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator, for use in a method of treatment as described herein.
In one aspect, the present disclosure provides for the use of an anti-DLK1 ADC and/or a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator 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 anti-DLK1 ADC may be as defined in the section herein entitled “Anti-DLK1 ADCs”. The anti-DLK1 ADC may be ADCT-701.
The individual may be undergoing treatment with a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator and/or have previously undergone treatment with the secondary agent. The individual may be refractory to treatment, or further treatment, with the secondary agent.
The anti-DLK1 ADC may be as defined in the section herein entitled “Anti-DLK1 ADCs”. The anti- DLK1 ADC may be ADCT-701 .
The first composition may be administered before the second composition, simultaneous with the second composition, or after the second composition.
Another aspect of the disclosure provides a kit comprising: a first medicament comprising an anti-DLK1 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 secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator.
Another aspect of the disclosure provides a kit comprising: a first medicament comprising an anti-DLK1 ADC; a second medicament comprising a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator; 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.
In a yet further aspect, the disclosure provides a composition comprising an anti-DLK1 ADC and a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator.
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 the composition comprising an anti-DLK1 ADC and a secondary agent selected from gemcitabine, a PARP inhibitor and a checkpoint modulator. In some cases, the method comprises administering to the individual an effective amount of the composition comprising an anti-DLK1 ADC and the secondary agent.
DETAILED DESCRIPTION Antibody Drug Conjugates (ADCs)
The present disclosure relates to the improved efficacy of combinations of an ADC and a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator.
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-proliferative 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 to treatment with an anti-DLK1 ADC disclosed in WO2018/146199, and as herein described.
Anti-DLK1 ADCs
As used herein, the term “DLK1 ADC” refers to an ADC in which the antibody component is an anti- DLK1 antibody. The term “PBD-ADC” refers to an ADC in which the drug component is a pyrrolobenzodiazepine (PBD) warhead. The term “anti-DLK1 ADC” refers to an ADC in which the antibody component is an anti-DLK1 antibody, and the drug component is a PBD warhead.
The ADC may comprise a conjugate of formula (I): Ab - (DL)P (I), wherein:
Ab is an antibody that binds to DLK1 ;
X is selected from the group comprising: a single bond, -CH2- and -C2H4-; n is from 1 to 8; m is 0 or 1 ;
R7 is either methyl or phenyl; when there is a double bond between C2 and C3, R2 is selected 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-Ci-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 R24 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 between C2 and C3, R2 is
, where R26a and R26b 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 C 1-4 alkyl ester; when there is a double bond between C2’ and C3’, R12 is selected 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-Ci-3 alkylene;
(ib) C1-5 saturated aliphatic alkyl;
(ic) C3-6 saturated cycloalkyl;
, wherein each of R31, R32 and R33 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 R35a and R35b 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 R24 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 between C ’ and C ’, R12 is
, where R36a and R36b 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 R36a and R36b is H, the other is selected from nitrile and a C 1-4 alkyl ester; and p is from 1 to 2.
The subscript p in the formula I is an integer of from 1 to 2. 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 2 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 2.
It has previously been shown that such ADCs are useful in the treatment of DLK1 expressing cancers (see, for example, WO2018/146199, which is incorporated by reference herein in its entirety).
The term anti-DLK1 ADC may include any embodiment described in WO2018/146199.
A preferred embodiment is a conjugate having the structure:
wherein the antibody (Ab) comprises (i) a VH domain having the sequence of SEQ ID N0.1 , and (ii) a VL domain having the sequence of SEQ ID NO.2.
In an aspect the antibody is an antibody as described herein which has been modified (or further modified) as described in, for example, WO2018/146199. In some embodiments the antibody is a humanised, deimmunised or resurfaced version of an antibody disclosed herein.
A preferred anti-DLK1 ADC for use with the aspects of the present disclosure is ADCT-701 .
Antibody
In one aspect the antibody is an antibody that binds to DLK1 .
HuBa-1-3d
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 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 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.
In preferred embodiments the antibody comprises a VH domain and a VL domain. Preferably the VH comprises the sequence of SEQ ID N0.1 and the VL domain comprises the sequence of SEQ ID NO.2.
The VH and VL domain(s) may pair so as to form an antibody antigen binding site that binds DLK1 .
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 N0.1 paired with 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. 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.
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. In some embodiments the antibody is an intact antibody comprising two heavy chains having the sequence of SEQ ID N0.11 , each paired with a light chain having the sequence of SEQ ID NO.4.
In one aspect the antibody is an antibody as described herein which has been modified (or further modified) as described in, for example, WO2018/146199. In some embodiments the antibody is a humanised, deimmunised or resurfaced version of an antibody disclosed herein.
In one exemplary embodiment, the antibody has been modified using GlycoConnect, or a similar technology, to trim N-linked glycans at Asn-297 (or its equivalent) with an endoglycosidase back to a core N-acetylglucosamine (GlcNAc) residue. A subsequent procedure using a b-1-4- galactosyltransferase and a sugar derivative (e.g. a UDP-GalNAc derivative containing a click chemistry reactive group, such as UDP-N-azidoacetylgalactosamine), results in the addition of a further sugar, such as N-acetylgalactosamine (GalNAc).
ADCT-701
ADCT-701 is an antibody drug conjugate composed of a humanized antibody against human DLK1 attached to a pyrrolobenzodiazepine (PBD) warhead via a cleavable linker. The mechanism of action of ADCT-701 depends on DLK1 binding. The DLK1 specific antibody targets the antibody drug conjugate (ADC) to cells expressing DLK1 .
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.
The antibody (Ab) represents Antibody HuBa-1-3-d having the VH and VL sequences SEQ ID NO. 1 and SEQ ID NO. 2, respectively. ADCT-701 is synthesised as described in WO2018/146199 and typically has a DAR (Drug to Antibody Ratio) of about 1.9.
The drug linker is typically conjugated to the antibody through the sidechain of the N-linked glycosylation site asparagine 297 via GlcNAc-GalNAc.
DLK1 binding
As used herein, “binds DLK1” is used to mean the antibody binds DLK1 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 DLK1 with an association constant (Ka) at least 2, 3, 4, 5, 10, 20, 50, 100 , 200 , 500, 1000 , 2000 , 5000, 104, 10s or 106-fold higher than the antibody’s association constant for BSA, when measured at physiological conditions. The antibodies of the invention can bind DLK1 with a high affinity. For example, in some embodiments the antibody can bind DLK1 with a KD equal to or less than about 106 M, such as 1 x 10_e, 107, 108, 10-9, 10-10, 1011 , 1012, 10-13 or
10-M
DLK1 is member of the EGF-like family of homeotic proteins. In some embodiments, the DLK1 polypeptide corresponds to Genbank accession no. CAA78163, version no. CAA78163.1 , record update date: Feb 2, 2011 10:34 AM (SEQ ID NO.12). In one embodiment, the nucleic acid encoding DLK1 polypeptide corresponds to Genbank accession no. Z12172, version no Z12172.1 , record update date: Feb 2, 2011 10:34 AM.
Secondary Agents
Gemcitabine
The combination of agents with different action mechanisms is an established therapeutic principle for combating cancer. It can be a way of increasing anti-tumour activity when a synergic effect is shown and/or when reduced toxicity is observed. Antibody-drug conjugates, including those with a
PBD warhead, may be particularly suited as combination partners because they are more targeted compared to conventional chemotherapy.
Gemcitabine is a broad-spectrum antimetabolite and deoxycytidine analogue with antineoplastic activity. Upon administration, gemcitabine is converted into the active metabolites difluorodeoxycytidine diphosphate (dFdCDP) and difluorodeoxycytidine triphosphate (dFdCTP) by deoxycytidine kinase. dFdCTP competes with deoxycytidine triphosphate (dCTP) and is incorporated into DNA. This locks DNA polymerase thereby resulting in masked termination during DNA replication. On the other hand, dFdCDP inhibits ribonucleotide reductase, thereby decreasing the deoxynucleotide pool available for DNA synthesis. The reduction in the intracellular concentration of dCTP potentiates the incorporation of dFdCTP into DNA.
Gemcitabine has shown activity in a variety of solid tumors and has been approved for the treatment of non-small cell lung cancer, pancreatic, bladder, and breast cancer. Recent data showed that gemcitabine is also active against ovarian cancer. Gemcitabine is reported to have a good toxicity profile, with myelosuppression being the most common side effect, while non-hematological events are relatively uncommon (Toschi et al., 2005, Future Oncology, Vol.1 (1), pp.7-17).
PBDs are a class of naturally occurring anti-tumour 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 tumour cell death. As PBD dimers cross-link DNA in a covalent fashion, combining them with other agents that interfere with DNA synthesis via a different mechanism, such as gemcitabine, is likely to provide a benefit. Tumours expressing DLK1 can be targeted for killing by this mechanism by using a PBD-based DLK1 -targeting ADC, such as ADCT-701 , in combination with Gemcitabine.
An anti-DLK-1-ADC such as ADCT-701 and Gemcitabine can be used to target and directly kill DLK1 (+) cancer cells. Next to DLK-1 (+) tumour cells, DLK-1 (-) tumour cells in close proximity to DLK-1 (+) tumour cells will potentially be killed by the bystander mechanism of the PBD-dimer released after cell kill of DLK-1 (+) cells and Gemcitabine. The resulting release of tumour associated antigens from cells that are killed with the PBD dimer will trigger the immune system.
The combination therapy disclosed herein is effective against cancers which do not express DLK1 . DLK1 is expressed on immune cells that infiltrate the local tumour environment and which can have a suppressive impact on the innate immune response against the tumour. Examples are Tregs, NK cells, DC cells or macrophages. An anti-DLK-1-ADC such as ADCT-701 can be used to target these immune cells, which on the one hand will kill the immune suppressive cells, boosting the immune response. Also, killing of the immune cells by ADCT-701 will release local PBD warhead which is able to kill subsequent neighbouring cells via bystander kill. Hence, tumours not expressing DLK1 can be killed by targeting immune cells in the local tumour environment. Also, targeting DLK1 negative tumour cells killed by PBD released from neighbouring immune cells will induce immunogenic cell death further strengthening the anti-tumour immune response.
To show that treatment of solid tumour-derived cell lines with PBD-based ADCs and gemcitabine has an additive or synergistic anti-tumour effect, a panel of solid tumour-derived cell lines will be treated with a range of concentration of each ADC and gemcitabine. 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 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, Niraparib, Pamiparib, 3-Aminobenzamide and E7016) 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 auto-modification 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 (Liglll), DNA polymerase beta (roΐb), and scaffolding proteins such as X-ray cross-complementing 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).
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.
PARP is inactivated by caspase-3 cleavage during programmed cell death.
PBDs are a class of naturally occurring anti-tumour 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 tumour 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 tumours as opposed to normal tissues.
Combining PBD-based ADCs with PARPi (including but not limited to Olaparib, CEP-9722, Talazoparib, Rucaparib, Iniparib, Veliparib, Niraparib, Pamiparib, 3-Aminobenzamide and E7016) is advantageous because repair of the DNA damage caused by the PBD dimers is blocked by the PARP inhibition hence resulting in accumulation of DNA damage leading to cancer cell death. Tumours expressing DLK1 can be targeted for killing by this mechanism by using a PBD-based DLK1 -targeting ADC, such as ADCT-701 , in combination with a PARP inhibitor (including but not limited to Olaparib, CEP-9722, Talazoparib, Rucaparib, Iniparib, Veliparib, Niraparib, Pamiparib, 3- Aminobenzamide and E7016).
An anti-DLK-1-ADC such as ADCT-701 can be used to target and directly kill DLK1 (+) cancer cells. Next to DLK-1 (+) tumour cells, DLK-1 (-) tumour cells in close proximity to DLK-1 (+) tumour cells will potentially be killed by the bystander mechanism of the PBD-dimer released after cell kill of DLK- 1 (+) cells. The resulting release of tumour associated antigens from cells that are killed with the PBD dimer will trigger the immune system.
The combination therapy disclosed herein is effective against cancers which do not express DLK1 . DLK1 is expressed on immune cells that infiltrate the local tumour environment and which can have a suppressive impact on the innate immune response against the tumour. Examples are Tregs, NK cells, DC cells or macrophages. An anti-DLK-1-ADC such as ADCT-701 can be used to target these immune cells, which on the one hand will kill the immune suppressive cells, boosting the immune response. Also, killing of the immune cells by an anti-DLK-1-ADC such as ADCT-701 will release local PBD warhead which is able to kill subsequent neighbouring cells via bystander kill. Hence, tumours not expressing DLK1 can be killed by targeting immune cells in the local tumour environment. Also, target negative tumour cells killed by PBD released from neighbouring immune cells will induce immunogenic cell death further strengthening the anti-tumour immune response.
To show that treatment of solid tumour-derived cell lines with PBD-based ADCs and PARPi has an additive or synergistic anti-tumour effect, a panel of solid tumour-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 which 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%.
Ahttp://www.fda.gov/Forlndustry/DataStandards/SubstanceRegistrationSystem-
UniquelngredientldentifierUNII/default.htm
Olaparib is a particularly preferred PARPi for use in the methods of the present disclosure.
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.
Checkpoint modulators
“Immune checkpoint molecules” are modulators of the anti-tumour immune response. Their interaction may activate or inhibit either activating or inhibitory immune signalling pathways. Immune checkpoint molecules may be present a variety of cell types, including but not limited to T cells, antigen-presenting cells and tumour cells. Examples of inhibitory immune checkpoint molecules include PD-1 and CTLA-4. Examples of activatory immune checkpoint molecules include 0X40 and GITR.
As used herein, “checkpoint modulator” means any chemical compound or biological molecule that stimulates an immune reaction through inhibition of inhibitory checkpoint molecule signalling (including but not limited to PD-1 signalling, CTLA-4 signalling, LAG-3 signalling, TIM-3 signalling, or TIGIT signalling) or through activation of activatory checkpoint signalling (including but not limited to 0X40 signalling and GITR signalling).
A “checkpoint modulator” may interact with an immune checkpoint molecule, or a ligand to which an immune checkpoint molecule binds, to inhibit checkpoint molecule signalling. For example, inhibition of PD-1 signalling can be achieved using a checkpoint modulator which targets PD-1 (e.g. Nivolumab) and/or a checkpoint modulator which targets PD-L1 (e.g. Atezolumab).
A “checkpoint modulator” may interact with an immune checkpoint molecule, or a ligand to which an immune checkpoint molecules binds, to stimulate checkpoint molecule signalling. For example,
activation of 0X40 signalling can be achieved using a checkpoint modulator which activates the costimulatory molecule 0X40, such as an 0X40 agonist.
PD1 inhibitors
Programmed death receptor I (PD1) is an immune-inhibitory receptor that is primarily expressed on activated T and B cells. Interaction with its ligands has been shown to attenuate T-cell responses both in vitro and in vivo. Blockade of the interaction between PD1 and one of its ligands, PD-L1 , has been shown to enhance tumour-specific CD8+ T-cell immunity and may therefore be helpful in clearance of tumour cells by the immune system.
PD1 (encoded by the gene Pdcdl) is an Immunoglobulin superfamily member related to CD28, and CTLA-4. PD1 has been shown to negatively regulate antigen receptor signalling upon engagement of its ligands (PD-L1 and/or PD-L2). The structure of murine PD1 has been solved as well as the cocrystal structure of mouse PD1 with human PD-L1 (Zhang, X., et al., (2004) Immunity 20: 337-347; Lin, et al., (2008) PNAS 105: 30I I-6). PD1 and like family members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail that is responsible for the binding of signaling molecules. The cytoplasmic tail of PD1 contains two tyrosine-based signaling motifs, an ITIM (immunoreceptor tyrosine-based inhibition motif) and an ITSM (immunoreceptor tyrosine-based switch motif).
In humans, expression of PD1 (on tumour infiltrating lymphocytes) and/or PD-L1 (on tumour cells) has been found in a number of primary tumour biopsies assessed by immunohistochemistry. Such tissues include cancers of the lung, liver, ovary, cervix, skin, colon, glioma, bladder, breast, kidney, esophagus, stomach, oral squamous cell, urothelial cell, and pancreas as well as tumours of the head and neck (Brown, J. A., et al., (2003) J Immunol. I 70: I257-I266; Dong H., et al., (2002) Nat. Med. 8: 793-800; Wintterle, et al., (2003) Cancer Res. 63: 7462-7467; Strome, S. E., et al., (2003) Cancer Res. 63: 650I-6505; Thompson, R.H., et al., (2006) Cancer Res. 66: 338I-5; Thompson, et al., (2007) Clin. Cancer Res. 13: I 757-6I; Nomi, T„ et al., (2007) Clin. Cancer Res. 13: 2I5I-7). More strikingly, PD-ligand expression on tumour cells has been correlated to poor prognosis of cancer patients across multiple tumour types (reviewed in Okazaki and Honjo, (2007) Int. Immunol. I9: 813- 824).
To date, numerous studies have shown that interaction of PD1 with its ligands (PD-L1 and PD-L2) leads to the inhibition of lymphocyte proliferation in vitro and in vivo. Blockade of the PD1/PD-L1 interaction could lead to enhanced tumour-specific T-cell immunity and therefore be helpful in clearance of tumour cells by the immune system. To address this issue, a number of studies were performed. In a murine model of aggressive pancreatic cancer (Nomi, T., et al. (2007) Clin. Cancer Res. 13: 2I5I-2I57), the therapeutic efficacy of PD1/PD-L1 blockade was demonstrated. Administration of either PD1 or PD-L1 directed antibody significantly inhibited tumour growth. Antibody blockade effectively promoted tumour reactive CD8+ T cell infiltration into the tumour resulting in the up-regulation of anti-tumour effectors including IFN gamma, granzyme Band perforin. Additionally, the authors showed that PD1 blockade can be effectively combined with chemotherapy to yield a synergistic effect. In another study, using a model of squamous cell carcinoma in mice, antibody blockade of PD1 or PD-L1 significantly inhibited tumour growth (Tsushima, F., et al., (2006) Oral Oneal. 42: 268-274).
"PD1 antagonist" means any chemical compound or biological molecule that stimulates an immune reaction through inhibition of PD1 signalling.
To examine the extent of enhancement or inhibition of, e.g., PD1 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%. Enhancement is achieved when the activity value relative to the control is about 110%, generally at least 120%, more generally at least 140%, more generally at least 160%, often at least 180%, more often at least 2-fold, most often at least 2.5-fold, usually at least 5-fold, more usually at least 10-fold, preferably at least 20-fold, more preferably at least 40- fold, and most preferably over 40-fold higher.
The major function of PD1 is to limit the activity of T-cells at the time of an anti-inflammatory response to infection and to limit autoimmunity. PD1 expression is induced when T-cells become activated, and binding of one of its own ligands inhibits kinases involved in T-cell activation. Hence, in the tumour environment this may translate into a major immune resistance, because many tumours are highly infiltrated with TReg cells that further suppress effector immune responses. This resistance mechanism is partially alleviated by the use of PD1 inhibitors in combination with the ADC.
PBDs are a class of naturally occurring anti-tumour 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 tumour 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 tumours as opposed to normal tissues.
CTLA-4 inhibitors
CTLA-4 is a receptor found on surface of activated T-cells and regulatory T-cells (Tregs). CTLA-4 mainly acts by competing with CD28 receptors for binding to B7 ligands (B7-1/CD80 and B7- 2/CD86) on antigen presenting cells (APCs). During T-cell activation, CD28 receptors on T-cells bind to B7 ligands on APCs and provide the essential second activation signal for T-cells. However, CTLA-4 receptors bind to B7 ligands with higher affinity and at a lower surface density and thereby outcompete CD28 receptors for binding with B7 ligands. CTLA-4 receptors also sequester B7- ligands from the surface of the APCs and result in significant depletion of the ligands on their surface.
CTLA-4 interacts with B7 ligands to transduce a signal leading to inactivation of T cells bearing the CTLA-4 receptor. Disruption of this interaction effectively induces, enhances or prolongs the activation of such T cells, thereby inducing, enhancing or prolonging an immune response.
“CTLA-4 antagonist” means any chemical compound or biological molecule that stimulates an immune reaction through inhibition of CTLA-4 signalling.
0X40
0X40 (CD134) is an activating receptor expressed by Treg cells, activated T cells and NK cells. 0X40 binds OX40L (CD252), which is expressed on numerous cell types including B cells, neutrophils, endothelial cells, mast cells dendritic cells and monocytes. The OX40-OX40L pathway can inhibit Treg function and activate CD8+ T cells.
ΌC40 agonist” means any chemical compound or biological molecule that stimulates an immune reaction through activation of 0X40 signalling.
GITR
GITR is expressed in various T cell types, including T lymphocytes. The GITR-GITR ligand (GITRL) pathway can inhibit Treg function and activate CD8+ T cells.
“GITR agonist” means any chemical compound or biological molecule that stimulates an immune reaction through activation of GITR signalling.
Other targets
Alternative inhibitory receptors such as LAG-3, TIM-3 and TIGIT have also been identified as targets for anti-tumour immune therapy.
LAG-3 is expressed on CD4 T cells, CD8 T cells and NK cells. LAG-3 interacts with MHC class II and LSECtin expressed on antigen-presenting cells, liver cells, and some tumour cells.
"LAG-3 antagonist" means any chemical compound or biological molecule that stimulates an immune reaction through inhibition of LAG-3 signalling.
TIM-3 is expressed on CD4 T cells, CD8 T cells, dendritic cells, natural killer cells, monocytes and macrophages. TIM-3 binds to ligands such as galectin-9, phosphatidyl esrine, high mobility group protein B1 , and Ceacam-1 expressed on endothelial cells, apoptotic cells, and some tumour cells.
"TIM-3 antagonist" means any chemical compound or biological molecule that stimulates an immune reaction through inhibition of TIM-3 signalling.
TIGIT is expressed on CD4 T cells, CD8 T cells and NK cells. TIGIT interacts with CD155 (PVR) and CD122 (PVRL2, nectin-2) expressed on antigen-presenting cells, T cells and some tumour cells.
"TIGIT antagonist" means any chemical compound or biological molecule that stimulates an immune reaction through inhibition of TIGIT signalling.
Rationale behind combination therapy
The present authors believe that the administration of a combination of an anti-DLK1 ADC and checkpoint modulator to an individual leads to unexpected clinical advantages. The rationale behind the unexpected clinical advantages of combining an anti-DLK1 ADC with a checkpoint inhibitor (for example, PD1 antagonists, PD-L1 antagonists and CTLA-4 antagonists) or a checkpoint activator (for example, 0X40 agonists and GITR agonists) are discussed below using specific examples.
However, many of the considerations discussed in relation to the specific examples are relevant and applicable to other types of checkpoint modulator. For instance, in all combination therapies disclosed herein, an anti-DLK-1-ADC such as ADCT-701 can be used to target and directly kill DLK1 (+) cancer cells. Next to DLK-1 (+) tumour cells, DLK-1 (-) tumour cells in close proximity to DLK-1 (+) tumour cells will potentially be killed by the bystander mechanism of the PBD-dimer released after cell kill of DLK-1 (+) cells. The resulting release of tumour associated antigens from cells that are killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use checkpoint modulators.
PD1 antagonists
Combining ADCT-701 , which targets DLK-1- positive tumours, with PD1 inhibitors is advantageous, because on the one hand, ADCT-701 will directly kill the DLK-1 -positive tumour cells, while on the other hand the PD1 inhibitor will engage the patient’s own immune system to eliminate the cancer cells. Next to DLK-1 (+) tumour cells, DLK-1 (-) tumour cells in close proximity to DLK-1 (+) tumour cells will potentially be killed by the bystander mechanism of the PBD-dimer released after cell kill of DLK-1 (+) cells. Hence, ADCT-701 will directly kill the tumour cells. The resulting release of tumour associated antigens from cells that are killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use of programmed cell death protein 1 (PD1) inhibitors, expressed on a large proportion of tumour infiltrating lymphocytes (TILs) from many different tumour types. Blockade of the PD1 pathway may enhance antitumour immune responses against the antigens released from the tumours killed by ADCT-701 by diminishing the number and/or suppressive activity of intratumoural TReg cells. The major function of PD1 is to limit the activity of T-cells at the time of an anti-inflammatory response to infection and to limit autoimmunity. PD1 expression is induced when T-cells become activated, and binding of one of its own ligands inhibits kinases involved in T-cell activation. Hence, in the tumour environment this may translate into a major immune resistance, because many tumours are highly infiltrated with TReg cells that probably further suppress effector immune responses. This resistance mechanism is alleviated by the use of PD1 inhibitors in combination with ADCT-701.
PD-L1 antagonists
Combining ADCT-701 , which targets DLK-1 -positive tumours, with PDL1 inhibitors is advantageous, because on the one hand, ADCT-701 will directly kill the DLK-1 -positive tumour cells, while on the other hand the PDL1 inhibitor will engage the patient’s own immune system to eliminate the cancer cells. Next to DLK-1 (+) tumour cells, target negative tumour cells in close proximity to DLK-1 (+) tumour cells will potentially be killed by the bystander mechanism of the PBD-dimer released after cell kill of DLK-1 (+) cells. Hence, ADCT-701 will directly kill the tumour cells. The resulting release of tumour associated antigens from cells that are killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use of programmed cell death protein 1 ligand inhibitors (PD-L1 , aka B7-H1 or CD274 ). PDL1 is commonly upregulated on the tumour cell surface from many different human tumours. Interfering with the PD1 ligand expressed on the tumour will avoid the immune inhibition in the tumour microenvironment and therefore blockade of the PD1 pathway using PDL1 inhibitors may enhance antitumour immune responses against the antigens released from the tumours killed by ADCT-701 .
CTLA4 antagonists
Combining ADCT-701 , which targets DLK1 positive lymphomas and leukemias, with CTLA4 inhibitors is advantageous, because on the one hand, ADCT-701 will directly kill the DLK1 positive
tumour cells, while on the other hand the CTLA4 inhibitor will engage the patient’s own immune system to eliminate the cancer cells. Next to DLK1 (+) tumour cells, target negative tumour cells in close proximity to DLK1 (+) tumour cells will potentially be killed by the bystander mechanism of the PBD-dimer released after cell kill of DLK1(+) cells. Hence, ADCT-701 will directly kill the tumour. The resulting release of tumour associated antigens from cells killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use of CTLA4 inhibitors expressed on a large proportion of tumour infiltrating lymphocytes (TILs) from many different tumour types. The major function of CTLA4 (CD152) is to regulate the amplitude of the early stages of T cell activation, and as such it counteracts the activity of the T cell co-stimulatory receptor, CD28, In the tumour microenvironment. Blockade of the CTLA4 pathway may therefore enhance enhancement of effector CD4+T cell activity, while it inhibits Treg cell-dependent immunosuppression. Therefore it will be beneficial to target a DLK1 (+) tumour with ADCT-701 , causing the antigenic cell death, while the CTLA4 blockade induces a stronger immune, durable response.
0X40 agonists
Combining ADCT-701 , which targets DLK1 positive lymphomas and leukemias, with 0X40 agonists is advantageous, because on the one hand ADCT-701 will directly kill the DLK1 positive tumour cells, while on the other hand the 0X40 agonist will engage the patient’s own immune system to eliminate the cancer cells. Next to DLK1 (+) tumour cells, target negative tumour cells in close proximity to DLK1 (+) tumour cells will potentially be killed by the bystander mechanism of the PBD- dimer released after cell kill of DLK1 (+) cells. Hence, ADCT-701 will directly kill the tumour. The resulting release of tumour associated antigens from cells killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use of a 0X40 agonist. 0X40 (CD134; TNFRSF4) is a member of the TNFR super-family and is expressed by CD4 and CD8 T cells during antigen-specific priming. 0X40 expression is largely transient following TCR/CD3 cross-linking, and by the presence of inflammatory cytokines. In the absence of activating signals, relatively few mature T cell subsets express 0X40 at biologically relevant levels. Generating optimal “killer” CD8 T cell responses requires T cell receptor activation plus co-stimulation, which can be provided through ligation of 0X40 using a 0X40 agonist. This activating mechanism augments T cell differentiation and cytolytic function leading to enhanced anti-tumour immunity. Therefore it will be beneficial to target a DLK1 (+) tumour with ADCT-701 , causing the antigenic cell death, while the 0X40 agonist induces a stronger, durable immune response.
GITR agonists
Combining ADCT-701 , which targets DLK1 positive lymphomas and leukemias, with GITR agonists is advantageous, because on the one hand ADCT-701 will directly kill the DLK1 positive tumour cells, while on the other hand the GITR agonist will engage the patient’s own immune system to eliminate the cancer cells. Next to DLK1 (+) tumour cells, target negative tumour cells in close proximity to DLK1 (+) tumour cells will potentially be killed by the bystander mechanism of the PBD- dimer released after cell kill of DLK1 (+) cells. Hence, ADCT-701 will directly kill the tumour. The resulting release of tumour associated antigens from cells killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use of a GITR agonist. GITR (Glucocorticoid- induced tumour-necrosis-factor-receptor-related protein) is expressed transiently on activated T cells and expressed constitutively at high levels on Tregs with further induction following activation. GITR ligation via its ligand GITRL stimulates both proliferation and function of both effector and regulatory CD4+ T cells. This promotes T-cell survival, and differentiation into effector cells, while abrogating
suppression. Therefore it will be beneficial to target a DLK1 (+) tumour with ADCT-701 , causing the antigenic cell death, while the GITR agonist induces a stronger, durable immune response.
DLK1 is also expressed on immune cells that infiltrate the local tumour environment and which can have a suppressive impact on the innate immune response against the tumour. Examples are Tregs, NK cells, DC cells or macrophages. An anti-DLK-1-ADC such as ADCT-701 can be used to target these immune cells, which on the one hand will kill the immune suppressive cells, boosting the immune response. Also, killing of the immune cells by ADCT-701 will release local PBD warhead which is able to kill subsequent neighbouring cells via bystander kill. Hence, tumours not expressing DLK1 can be killed by targeting immune cells in the local tumour environment. Also, target negative tumour cells killed by PBD released from neighbouring immune cells will induce immunogenic cell death further strengthening the anti-tumour immune response. These considerations are relevant and applicable to all of the combination therapies disclosed herein.
PD1 antagonists
Combining ADCT-701 with PD1 inhibitors for treatment of DLK1 negative tumours is advantageous, because on the one hand, ADCT-701 will indirectly kill the DLK1 negative tumour cells via local bystander kill released from tumour infiltrating lymphocytes killed by ADCT-701 , while on the other hand the PD1 inhibitor will engage the patient’s own immune system to eliminate the cancer cells. The resulting release of tumour associated antigens from cells that are killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use of programmed cell death protein 1 (PD1) inhibitors, expressed on a large proportion of tumour infiltrating lymphocytes (TILs) from many different tumour types. Blockade of the PD1 pathway may enhance antitumour immune responses against the antigens released from the tumours killed by ADCT-701 by diminishing the number and/or suppressive activity of intratumoural Treg cells. The major function of PD1 is to limit the activity of T-cells at the time of an anti-inflammatory response to infection and to limit autoimmunity. PD1 expression is induced when T-cells become activated, and binding of one of its own ligands inhibits kinases involved in T-cell activation. Hence, in the tumour environment this may translate into a major immune resistance, because many tumours are highly infiltrated with TReg cells that probably further suppress effector immune responses. This resistance mechanism is alleviated by the use of PD1 inhibitors in combination with ADCT-701 .
PD-L1 antagonists
Combining ADCT-701 with PDL1 inhibitors for treatment of DLK1 negative tumours is advantageous, because on the one hand, ADCT-701 will indirectly kill the DLK1 negative tumour cells via local bystander kill released from tumour infiltrating lymphocytes killed by ADCT-701 , while on the other hand the PDL1 inhibitor will engage the patient’s own immune system to eliminate the cancer cells. The resulting release of tumour associated antigens from cells that are killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use of programmed cell death protein 1 ligand inhibitors (PD-L1 , aka B7-H1 or CD274 ). PDL1 is commonly upregulated on the tumour cell surface from many different human tumours. Interfering with the PD1 ligand expressed on the tumour will avoid the immune inhibition in the tumour microenvironment and therefore blockade of the PD1 pathway using PDL1 inhibitors may enhance antitumour immune responses against the antigens released from the tumours killed by ADCT-701 .
Blockade of the PDL1 pathway may enhance antitumour immune responses against the antigens released from the tumours killed by ADCT-701 by diminishing the number and/or suppressive
activity of intratumoural Treg cells. The major function of PD1 is to limit the activity of T-cells at the time of an anti-inflammatory response to infection and to limit autoimmunity. PD1 expression is induced when T-cells become activated, and binding of one of its own ligands inhibits kinases involved in T-cell activation. Hence, in the tumour environment this may translate into a major immune resistance, because many tumours are highly infiltrated with TReg cells that probably further suppress effector immune responses. This resistance mechanism is alleviated by the use of PD1 inhibitors in combination with ADCT-701.
CTLA4 antagonists
Combining ADCT-701 with CTLA4 inhibitors for treatment of DLK1 negative tumours is advantageous, because on the one hand, ADCT-701 will indirectly kill the DLK1 negative tumour cells via local bystander kill released from tumour infiltrating lymphocytes killed by ADCT-701 , while on the other hand the CTLA4 antagonist will engage the patient’s own immune system to eliminate the cancer cells. The resulting release of tumour associated antigens from cells killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use of CTLA4 inhibitors expressed on a large proportion of tumour infiltrating lymphocytes (TILs) from many different tumour types. The major function of CTLA4 (CD152) is to regulate the amplitude of the early stages of T cell activation, and as such it counteracts the activity of the T cell co-stimulatory receptor, CD28, In the tumour microenvironment. Blockade of the CTLA4 pathway may therefore enhance enhancement of effector CD4+T cell activity, while it inhibits TReg cell-dependent immunosuppression. Therefore it will be beneficial to target a DLK1 (+) tumour with ADCT-701 , causing the antigenic cell death, while the CTLA4 blockade induces a stronger immune, durable response.
0X40 agonists
Combining ADCT-701 with 0X40 agonists for treatment of DLK1 negative tumours is advantageous, because on the one hand, ADCT-701 will indirectly kill the DLK1 negative tumour cells via local bystander kill released from tumour infiltrating lymphocytes killed by ADCT-701 , while on the other hand the 0X40 agonist will engage the patient’s own immune system to eliminate the cancer cells. The resulting release of tumour associated antigens from cells killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use of a 0X40 agonist. 0X40 (CD134; TNFRSF4) is a member of the TNFR super-family and is expressed by CD4 and CD8 T cells during antigen-specific priming. 0X40 expression is largely transient following TCR/CD3 cross-linking, and by the presence of inflammatory cytokines. In the absence of activating signals, relatively few mature T cell subsets express 0X40 at biologically relevant levels. Generating optimal “killer” CD8 T cell responses requires T cell receptor activation plus co-stimulation, which can be provided through ligation of 0X40 using a 0X40 agonist. This activating mechanism augments T cell differentiation and cytolytic function leading to enhanced anti-tumour immunity. Therefore it will be beneficial to target a DLK1 (+) tumour with ADCT-701 , causing the antigenic cell death, while the 0X40 agonist induces a stronger, durable immune response.
GITR agonists
Combining ADCT-701 with GITR agonists for treatment of DLK1 negative tumours is advantageous, because on the one hand, ADCT-701 will indirectly kill the DLK1 negative tumour cells via local bystander kill released from tumour infiltrating lymphocytes killed by ADCT-701 , while on the other hand the GITR agonist will engage the patient’s own immune system to eliminate the cancer cells. The resulting release of tumour associated antigens from cells killed with the PBD dimer will trigger the immune system, which will be further enhanced by the use of a GITR agonist. GITR
(Glucocorticoid-induced tumour-necrosis-factor-receptor-related protein) is expressed transiently on activated T cells and expressed constitutively at high levels on Tregs with further induction following activation. GITR ligation via its ligand GITRL stimulates both proliferation and function of both effector and regulatory CD4+ T cells. This promotes T-cell survival, and differentiation into effector cells, while abrogating suppression. Therefore it will be beneficial to target a DLK1 (+) tumour with ADCT-701 , causing the antigenic cell death, while the GITR agonist induces a stronger, durable immune response.
To show that treatment of solid tumour-derived cell lines with PBD-based ADCs and checkpoint modulators has an additive or synergistic anti-tumour effect, a panel of solid tumour-derived cell lines will be treated with a range of concentration of each ADC and a checkpoint modulator. 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.
To examine the extent of inhibition of, e.g., PD1 activity or CTLA-4 activity, samples or assays comprising a given, e.g., protein, gene, cell, or organism, are treated with a potential 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%.
To examine the extent of activation of, e.g., 0X40 activity or GITR activity, samples or assays comprising a given, e.g., protein, gene, cell, or organism, are treated with a potential activating agent and are compared to control samples treated with an inactive control molecule. Control samples are assigned a relative activity value of 100%. Activation is achieved when the activity value relative to the control is about 110%, generally at least 120%, more generally at least 140%, more generally at least 160%, often at least 180%, more often at least 2-fold, most often at least 2.5- fold, usually at least 5-fold, more usually at least 10-fold, preferably at least 20-fold, more preferably at least 40-fold, and most preferably over 40-fold higher.
Ahttp://www.fda.gov/Forlndustry/DataStandards/SubstanceRegistrationSystem-
UniquelngredientldentifierUNII/default.htm
PD-1 antagonists, PD-L1 antagonists, CTLA-4 antagonists, 0X40 agonists, and GITR agonists are particularly preferred checkpoint modulators for use in the methods of the present disclosure. Nivolumab, Pembrolizumab, Cemiplimab, Atezolizumab, Durvalumab, Avelumab and Ipilimumab are particularly preferred checkpoint modulators for use in the methods of the present disclosure. Pembrolizumab is a particularly preferred checkpoint modulator for use in the methods of the present disclosure.
In some embodiments, PD1 polypeptide corresponds to Genbank accession no. AAC51773, version no. AAC51773.1 , record update date: Jun 23, 2010 09:24 AM. In one embodiment, the nucleic acid encoding PD1 polypeptide corresponds to Genbank accession no. U64863, version no. U64863.1 , record update date: Jun 23, 2010 09:24 AM. In some embodiments, PD1 polypeptide corresponds to Uniprot/Swiss-Prot accession No. Q15116.
In some embodiments, PDL1 polypeptide corresponds to Genbank accession no. AAI13735, version no. AAI13735.1. In one embodiment, the nucleic acid encoding PDL1 polypeptide corresponds to Genbank accession no. BC113734, version no. BC113734.1. In some embodiments, PDL1 polypeptide corresponds to Uniprot/Swiss-Prot accession No. Q9NZQ7.
In some embodiments, CTLA-4 polypeptide corresponds to Genbank accession no. AAD00698, version no. AAD00698.1. In one embodiment, the nucleic acid encoding CTLA-4 polypeptide corresponds to Genbank accession no. U90273, version no. U90273.1. In some embodiments, CTLA-4 polypeptide corresponds to Uniprot/Swiss-Prot accession No. P16410.
Advantageous properties of the described combinations
The secondary agent selected from gemcitabine. a PARP inhibitor and a checkpoint modulator when used as a single agent in isolation has demonstrated clinical utility - for example in the treatment of cancer. The efficacy of an anti-DLK1 ADC in the treatment of, for example, cancer has been established - see, for example, WO2018/146199. Based on their work with numerous PBD-
ADCs, the present authors believe that an anti-DLK1 ADC, such as ADCT-701 , would demonstrate clinical utility, for example in the treatment of cancer, when used as a single agent in isolation.
As described herein, combination of the anti-DLK1 ADC and a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator is expected to provide one or more of the following advantages over treatment with either anti-DLK1 ADC or the secondary agent 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.
5) increased tolerability
Effective treatment of a broader range of cancers as used herein means that following treatment with the combination a complete or partial response is observed with a greater range of recognised cancer types. That is, a complete or partial response is seen from cancer types not previously reported to completely respond to either anti-DLK1 ADC or the secondary agent alone.
Effective treatment of a resistant, refractory, or relapsed forms as used herein means that following treatment with the combination a complete or partial response is observed in individuals that are either partially or completely resistant or refractory to treatment with either anti-DLK1 ADC or the secondary agent 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 or partial response following treatment with the anti-DLK1 ADC / secondary agent combination is observed in at least 10%, 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-DLK1 ADC or the secondary agent alone.
Increased response rate to treatment as used herein means that following treatment with the combination a complete or partial response is observed in a greater proportion of individuals than is observed following treatment with either anti-DLK1 ADC or the secondary agent.
‘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.
‘Partial response’ is used herein to mean a reduction in any clinical evidence of disease in an individual. For instance, a partial response may mean a reduction in the size of a tumour, in the expression of tumour markers, or in the extent of cancer in the body. Evidence may be assessed using the appropriate methodology in the art, for example CT or PET scanning, or biopsy where appropriate. A partial response may mean at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45% or 50% decrease in the diameter of a tumour. The number of doses required to achieve partial response may be one, two, three, four, five, ten or more. In some embodiments the individuals achieve partial 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 tumour 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-DLK1 ADC which binds DLK1 for use in therapy, wherein the method comprises selecting a subject based on expression of the target protein.
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.
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 carcinoma, 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.
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. Examples of cancer to be treated herein include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. Cancers of particular interest include: squamous cell cancer (e.g. epithelial squamous cell cancer), hepatocellular carcinoma, hepatoblastoma, lung cancer, non small cell lung cancer, small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, breast cancer, ovarian cancer, gastric cancer, stomach cancer, gastrointestinal cancer, bowel cancer, colon cancer, rectal cancer, colorectal cancer, anal carcinoma, breast carcinoma, ovarian carcinoma, cervical cancer, endometrial or uterine carcinoma, vulval cancer, prostate cancer, testicular cancer, penile carcinoma, cancer of the peritoneum, liver cancer, cholangiacarcinoma, hepatocellular cancer, hepatocellular carcinoma, hepatoma, hepatic carcinoma, rhabdomyosarcoma, cholangiacarcinoma,
kidney cancer, renal cancer, bladder cancer, pancreatic cancer, head and neck cancer, brain cancer, sarcoma, osteosarcoma, Kaposi’s sarcoma, melanoma, neuroblastoma, glioblastoma, adrenal gland cancer, adrenalcortical carcinoma, salivary gland carcinoma, thyroid cancer, pheochromocytoma, paraganglioma, thyroid medullary cancer, thyroid medullary carcinoma, skeletal muscle cancer, liposarcoma, glioma, bone-derived cancer, Wilms tumour, neuroendocrine tumours, Acute Myeloid Leukemia and Myelodysplastic syndrome.
Cancers of particular interest include myelodysplastic syndrome, acute myeloid leukaemia, hepatoblastoma, small cell lung cancer, colon cancer, neuroblastoma, adrenal gland cancer, pheochromocytoma, paraganglioma and skeletal muscle tumour.
Cancers of particular interest include small cell lung cancer, neuroblastoma, adrenal gland cancer, pheochromocytoma and paraganglioma.
Other disorders of interest include any condition in which DLK1 is overexpressed, or wherein DLK1 antagonism will provide a clinical benefit. These include immune disorders, cardiovascular disorders, thrombosis, diabetes, immune checkpoint disorders, fibrotic disorders (fibrosis), or proliferative diseases such as cancer, particularly metastatic cancer.
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.
The proliferative disease may be characterised by the presence of a neoplasm comprising DLK1+ve cells. The proliferative disease may be characterised by the presence of a neoplasm comprising both DLK1+ve and DLK1-ve cells. The proliferative disease may be characterised by the presence of DLK1+ve non-neoplastic cells, for instance DLK1+ve tumour-associated non-tumour cells.
The target neoplasm or neoplastic cells may be all or part of a solid tumour, such as an advanced solid tumour.
Solid tumours may be neoplasms, including non-haematological cancers, comprising or composed of DLK1+ve neoplastic cells. Solid tumours may be neoplasms, including non-haematological cancers, comprising or composed of DLK1+ve neoplastic cells and DLK1-ve neoplastic cells. The solid tumour may be associated with DLK1+ve infiltrating cells. Solid tumours may be neoplasms, including non-haematological cancers, infiltrated with DLK1+ve cells.
It is contemplated that the antibody-drug conjugates (ADC) of the present invention may be used to treat various diseases or disorders, e.g. characterized by the overexpression of a tumour antigen. Exemplary conditions or hyperproliferative disorders include benign or malignant tumours; leukemia, haematological, and lymphoid malignancies. Others include neuronal, glial, astrocytal, hypothalamic, glandular, macrophagal, epithelial, stromal, blastocoelic, inflammatory, angiogenic and immunologic, including autoimmune, disorders.
Autoimmune diseases for which the ADC compounds may be used in treatment include rheumatologic disorders (such as, for example, rheumatoid arthritis, Sjogren's syndrome, scleroderma, lupus such as SLE and lupus nephritis, polymyositis/dermatomyositis,
cryoglobulinemia, anti-phospholipid antibody syndrome, and psoriatic arthritis), osteoarthritis, autoimmune gastrointestinal and liver disorders (such as, for example, inflammatory bowel diseases (e.g. ulcerative colitis and Crohn's disease), autoimmune gastritis and pernicious anemia, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and celiac disease), vasculitis (such as, for example, ANCA-associated vasculitis, including Churg-Strauss vasculitis, Wegener's granulomatosis, and polyarteriitis), autoimmune neurological disorders (such as, for example, multiple sclerosis, opsoclonus myoclonus syndrome, myasthenia gravis, neuromyelitis optica, Parkinson’s disease, Alzheimer’s disease, and autoimmune polyneuropathies), renal disorders (such as, for example, glomerulonephritis, Goodpasture’s syndrome, and Berger’s disease), autoimmune dermatologic disorders (such as, for example, psoriasis, urticaria, hives, pemphigus vulgaris, bullous pemphigoid, and cutaneous lupus erythematosus), hematologic disorders (such as, for example, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, post-transfusion purpura, and autoimmune hemolytic anemia), atherosclerosis, uveitis, autoimmune hearing diseases (such as, for example, inner ear disease and hearing loss), Behcet's disease, Raynaud's syndrome, organ transplant, and autoimmune endocrine disorders (such as, for example, diabetic-related autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM), Addison’s disease, and autoimmune thyroid disease (e.g. Graves’ disease and thyroiditis)). More preferred such diseases include, for example, rheumatoid arthritis, ulcerative colitis, ANCA- associated vasculitis, lupus, multiple sclerosis, Sjogren's syndrome, Graves’ disease, IDDM, pernicious anemia, thyroiditis, and glomerulonephritis.
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. Individuals may have, or be suspected of having, or be at risk of having, small cell lung cancer, neuroblastoma, adrenal gland cancer, pheochromocytoma or paraganglioma. 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-tumour cells that express DLK1 , such as infiltrating cells that express DLK1.
In some aspects, subjects are selected on the basis of the amount or pattern of expression of DLK1 . In some aspects, the selection is based on expression of DLK1 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 DLK1 . The neoplasm may be composed of cells having surface expression of DLK1.
In some aspects, subjects are selected on the basis they have a neoplasm comprising DLK1+ve cells. The neoplasm may comprise both DLK1+ve and DLK1-ve cells. The neoplasm may comprise DLK1+ve non-neoplastic cells. The neoplasm or neoplastic cells may be all or part of a solid tumour, such as an advanced solid tumour. The solid tumour may be infiltrated with DLK1+ve cells.
In some cases, expression of DLK1 in a particular tissue of interest is determined. For example, in a sample of tumour tissue. In some cases, systemic expression of DLK1 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 DLK1 expression in a sample. In those cases, subjects without DLK1 expression may be considered not suitable for treatment.
In other aspects, the level of DLK1 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 DLK1 as determined by immunohistochemistry (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 DLK1. 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 DLK1 .
In some aspects, the presence of DLK1 in cells in the sample indicates that the individual is suitable for treatment with a combination comprising an anti-DLK1 ADC and the secondary agent. In other aspects, the amount and/or expression of DLK1 must be above a threshold level to indicate that the individual is suitable for treatment. In some aspects, the observation that DLK1 expression 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 DLK1 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 DLK1. 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 DLK1.
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-DLK1 ADC if the individual has been treated with the secondary agent. In some embodiments the individual is selected for treatment with the anti-DLK1 ADC if the individual is being treated with the secondary agent. In some cases the individual is selected for treatment if they are refractory to treatment (or further treatment) with the secondary agent. In embodiments where the individual is undergoing, or has undergone, treatment with the secondary agent, the anti-DLK1 ADC may be administered in combination with the secondary agent, or without continued administration of the secondary agent.
In some embodiments the anti-DLK1 ADC is administered to the selected individual in combination with the secondary agent. In some embodiments the anti-DLK1 ADC is administered to the selected individual without continued administration of the secondary agent.
The term ‘refractory to treatment (or further treatment) with the secondary agent’ is used herein to mean that the disorder (such as cancer) does not respond, or has ceased to respond, to administration of the secondary agent when administered as a monotherapy.
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 tumour tissue, such as cancerous tumour tissue. The sample may have been obtained by a tumour 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 DLK1 .
Individual status
The individual may be an animal, such as a mammal, including 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 DLK1+ve cells.
The proliferative disease may be characterised by the presence of a neoplasm comprising DLK1+ve cells. The proliferative disease may be characterised by the presence of a neoplasm comprising both DLK1+ve and DLK1-ve cells. The proliferative disease may be characterised by the presence of DLK1+ve non-neoplastic cells, for instance DLK1+ve tumour-associated non-tumour cells.
In some cases, the individual has received a diagnosis of a solid tumour containing DLK1+ve infiltrating cells, such as an advanced solid tumour containing DLK1+ve infiltrating cells.
Solid tumours may be neoplasms, including non-haematological cancers, comprising or composed of DLK1+ve neoplastic cells. Solid tumours may be neoplasms, including non-haematological cancers, infiltrated with DLK1+ve cells. Solid tumours may be infiltrated with DLK1+ve nonneoplastic cells, for instance DLK1+ve tumour-associated non-tumour 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-701. In some cases the cancer is ovarian, breast, prostate or renal cancer. In some cases the cancer is small cell lung cancer, neuroblastoma, adrenocortical carcinoma, pheochromocytoma and paraganglioma.
The individual may be undergoing, or have undergone, treatment with the secondary agent. In some cases the individual may be refractory to treatment (or further treatment) with the secondary agent. In embodiments where the individual is undergoing, or has undergone, treatment with the secondary agent, the anti-DLK1 ADC may be administered in combination with the secondary agent, or without continued administration of the secondary agent.
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. The authors specifically contemplate that the “therapeutically-effective amount” or “effective amount” of the anti-DLK1 ADC and/or the secondary agent used in the combination therapy may be lower than the “therapeutically-effective amount” or “effective amount” of the anti-DLK1 ADC or the secondary agent used in monotherapy. The “therapeutically-effective amount” or “effective amount” of the anti-DLK1 ADC and/or the secondary agent used in the combination therapy may correspond to an amount of the anti-DLK1 ADC or the secondary agent which would be considered sub-optimal when used in monotherapy. Without wishing to be bound by theory, the authors believe this is due to a synergistic interaction between the anti-DLK1 ADC and the secondary agent.
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. The authors specifically contemplate that the “prophylactically-effective amount” or “effective amount” of the anti- DLK1 ADC and/or the secondary agent used in the combination therapy may be lower than the “prophylactically-effective amount” or “effective amount” of the anti-DLK1 ADC or the secondary agent used in monotherapy. The “prophylactically -effective amount” or “effective amount” of the anti-DLK1 ADC and/or the secondary agent used in the combination therapy may correspond to an amount of the anti-DLK1 ADC or the secondary agent which would be considered sub-optimal when used in monotherapy. Without wishing to be bound by theory, the authors believe this is due to a synergistic interaction between the anti-DLK1 ADC and the secondary agent.
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-DLK1 ADC and a secondary agent selected from gemcitabine, a PARP inhibitor and a checkpoint modulator. 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 time-course 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-DLK1 ADC comprises an anti-DLK1 antibody. The anti-DLK1 antibody may be HuBa-1-3d as disclosed herein. The ADC may comprise a drug which is a PBD dimer. The anti-DLK1 ADC may be as defined in the section herein entitled “Anti-DLK1 ADCs”. The ADC may be an anti-DLK1 ADC such as ADCT-701 . The ADC may be an ADC disclosed in WO2018/146199.
The treatment may involve administration of the anti-DLK1 ADC / secondary agent 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, the secondary agent;
(2) administering to the individual an anti-DLK1 ADC, such as ADCT-701 ; and, optionally
(3) administering to the individual the secondary agent in combination with the anti-DLK1 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/antitumour antibiotics,
topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors. Chemotherapeutic agents include compounds used in “targeted therapy” and conventional chemotherapy.
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-DLK1 ADC and/or the secondary agent, 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-DLK1 ADC is determined by the expression of DLK1 observed in a sample obtained from the subject. Thus, the level or localisation of expression of DLK1 in the sample may be indicative that a higher or lower dose of anti-DLK1 ADC is required. For example, a high expression level of DLK1 may indicate that a higher dose of anti-DLK1 ADC would be suitable. In some cases, a high expression level of DLK1 may indicate the need for administration of another agent in addition to the anti-DLK1 ADC. For example, administration of the anti-DLK1 ADC in conjunction with a chemotherapeutic agent. A high expression level of DLK1 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.
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 DLK1 . Antibodies may be murine, human, humanized, chimeric, or derived from other species such as rabbit, goat, sheep, horse or camel.
An 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 , G1 m2, G1 m3, non-G1 m1 [that, is any allotype other than G1 m1], 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-id) 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 et al (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 nonhuman primate (e.g. Old World Monkey or Ape) and human constant region sequences.
The antibodies herein may be modified (or further modified) as described in, for example, WO2018/146199.
SEQUENCE LISTING PART OF THE DESCRIPTION SEQ ID N0.1 [HuBa-1 -3d VH, CDR underline]
QVQLVQSGAEVKKPGASVKVSCKGSGYTFTDYAMHWVRQAPGQGLEWIGVISTYYGNTNYNQKF
KGKATMTVDKSTSTAYMELRSLRSDDTAVYYCARGGLREYYYAMDYWGQGTMVTVSS
SEQ ID NO.2 [HuBa-1 -3d VL, CDR underline]
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSSNQKNYLAWYQQKPGQPPKLLVYFASTRESGVPD
RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHYSTPPTFGQGTKLEIK
SEQ ID NO.3 [HuBa-1 -3d Heavy Chain]
QVQLVQSGAEVKKPGASVKVSCKGSGYTFTDYAMHWVRQAPGQGLEWIGVISTYYGNTNYNQKF
KGKATMTVDKSTSTAYMELRSLRSDDTAVYYCARGGLREYYYAMDYWGQGTMVTVSSASTKGPS
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP
EVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKC
KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
SEQ ID NO.4 [HuBa-1 -3d Light Chain]
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSSNQKNYLAWYQQKPGQPPKLLVYFASTRESGVPD
RFSGSGSGTDFTLTISSLQAEDVAVYYCQQHYSTPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKS
GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY
ACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO.5 [HuBa-1 -3d VH CDR1]
DYAMH
SEQ ID NO.6 [HuBa-1 -3d VH CDR2]
VISTYYGNTNYNQKFKG
SEQ ID NO.7 [HuBa-1 -3d VH CDR3]
GGLREYYYAMDY
SEQ ID NO.8 [HuBa-1 -3d VL CDR1]
KSSQSLLNSSNQKNYLA
SEQ ID NO.9 [HuBa-1 -3d VL CDR2]
FASTRES
SEQ ID NO.10 [HuBa-1 -3d VL CDR3]
QQHYSTPPT
SEQ ID N0.11 [HuBa-1 -3d Heavy Chain, terminal K]
QVQLVQSGAEVKKPGASVKVSCKGSGYTFTDYAMHWVRQAPGQGLEWIGVISTYYGNTNYNQKF
KGKATMTVDKSTSTAYMELRSLRSDDTAVYYCARGGLREYYYAMDYWGQGTMVTVSSASTKGPS
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP
EVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKC
KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
EXAMPLES
Example 1 : Prophetic in vitro study of ADCT-701 and Gemcitabine
ADCT-701 is an anti-DLK1 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, Zammarchi et al. AACR Annual Meeting 2018, April 14-18, Chicago, lllionis, and as described herein).
In vitro, the combination of ADCT-701 and gemcitabine will be evaluated in DLK1 -expressing cancer cell lines. Increasing concentration of ADCT-701 and gemcitabine will be tested either as single agents or in combination. After an incubation period of the test items with the cells of 3-7 days, the combination index will be calculated according to the Chou-Talalay method. Analysis of the median combination index values will be used to determine if the combination of ADCT-701 and gemcitabine has synergistic/additive/non beneficial activity.
Example 2: Prophetic in vivo study of ADCT-701 and Gemcitabine
The purpose of this proposed study is to assess the in vivo efficacy of combination therapies in which an anti-DLK1 ADC is administered in combination with Gemcitabine.
The combination between ADCT-701 and gemcitabine will be tested in mice implanted with DLK-1- expressing tumour cells. Once the tumours will have reached a mean tumour volume of 100-300 mm3· ADCT-701 and gemcitabine will be administered either as single agents or in combination. In the combination setting, ADCT-701 can be administered either concomitantly with gemcitabine or after a certain time interval after gemcitabine dosing has started. Typically, ADCT-701 is dosed as a single dose between 0.1 and 1 mg/kg, while gemcitabine is dosed q3dx4 or q7dx4 at doses between 10 and 240 mg/kg. Tumour volumes and body weights of the mice will be measured for at least 30 days. The anti-tumour activity of the single agents and of the combination of the two agents will be assessed by determining tumour volumes over study duration, number of responders (partial responder, complete responder and tumour-free survivor) and survival benefit (log-rank test) at the end of the study. The coefficient of drug interaction (CDI), which will be calculated when at least 50% of the mice will be present in each group, will determine if the combination of the 2 drugs has synergistic/additive/non beneficial anti-tumour activity.
Example 3: Prophetic in vitro study of ADCT-701 and Olaparib
ADCT-701 is an anti-DLK1 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, Zammarchi et al. AACR Annual Meeting 2018, April 14-18, Chicago, lllionis, and as described herein).
In vitro, the combination of ADCT-701 and Olaparib will be evaluated in DLK1 -expressing cancer cell lines (either BRCA1/2 wild-type or mutated). Increasing concentration of ADCT-701 and Olaparib will be tested either as single agents or in combination. After an incubation period of the test items with the cells of 3-7 days, the combination index will be calculated according to the Chou- Talalay method. Analysis of the median combination index values will be used to determine if the combination of ADCT-701 and Olaparib has synergistic/additive/non beneficial activity.
Example 4: Prophetic in vivo study of ADCT-701 and Olaparib
The purpose of this proposed study is to assess the in vivo efficacy of combination therapies in which an anti-DLK1 ADC is administered in combination with a PARP inhibitor.
The combination between ADCT-701 and Olaparib will be tested in mice implanted with DLK-1- expressing tumour cells (either BRCA1/2 wild-type or mutated). Once the tumours will have reached a mean tumour volume of 100-300 mm3, ADCT-701 and Olaparib will be administered either as single agents or in combination. Typically, ADCT-701 is dosed as a single dose between 0.1 and 1 mg/kg, while olaparib is dosed daily for 2-5 weeks at doses between 10 and 100 mg/kg. Tumour volumes and body weights of the mice will be measured for at least 30 days. The anti-tumour activity of the single agents and of the combination of the two agents will be assessed by determining tumour volumes over study duration, number of responders (partial responder, complete responder and tumour-free survivor) and survival benefit (log-rank test) at the end of the study. The coefficient of drug interaction (CDI), which will be calculated when at least 50% of the mice will be present in each group, will determine if the combination of the 2 drugs has synergistic/additive/non beneficial anti-tumour activity.
Example 5: Prophetic in vivo study of a PBD-based ADC against DLK1-701 and checkpoint modulator
Example 5.1 : tumours expressing DLK1
To test whether a PBD-based ADC against DLK1 combined with a checkpoint modulator shows additive or synergistic effect, the combination is tested in vivo in a syngeneic tumour model in immunocompetent mice. For this purpose, an antibody cross reactive with mouse DLK-1 is site- specifically conjugated using GlycoConnect™ technology to PL1601 , which contains HydraSpace™, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is coadministered with the checkpoint modulator to mice grafted with a mouse tumour cell line expressing DLK-1. Alternatively, syngeneic models using mouse cell lines genetically engineered to express human DLK1 are used, for treatment with ADCT-701 . Typically, the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the checkpoint modulator is dosed Q3d x 3 at doses between 1 and 10 mg/kg. Control groups include the ADC or checkpoint modulator alone. Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group. Statistical analysis (typically a log-rank test) is performed to determine whether the mice treated with the combination have outperformed the mice treated with either ADCT-701 or checkpoint modulator alone.
Example 5.2: tumours not expressing DLK1
To test whether a PBD-based ADC against DLK1 combined with a checkpoint modulator shows additive or synergistic effect against tumours not expressing DLK1 , the combination is tested in vivo in a syngeneic tumour model in immunocompetent mice. For this purpose, an antibody cross reactive with mouse DLK-1 is site-specifically conjugated using GlycoConnect™ technology to PL1601 , which contains HydraSpace™, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is co-administered with the checkpoint modulator to mice grafted with a mouse tumour cell line know to have high levels of infiltrating lymphocytes, such as but not limited to MC38 and CT26. Typically, the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the checkpoint modulator is dosed Q3d x 3 at doses between 1 and 10 mg/kg. Control groups include the ADC or checkpoint modulator alone. Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group. Statistical analysis (typically a log-rank test) is performed to determine whether the mice treated with the combination have outperformed the mice treated with either ADC or checkpoint modulator alone.
Example 6: Prophetic in vivo study of a PBD-based ADC against DLK1 and a PD1 antagonist
Example 6.1 : tumours expressing DLK1
To test whether a PBD-based ADC against DLK1 combined with a PD1 inhibitor shows additive or synergistic effect, the combination is tested in vivo in a syngeneic tumour model in immunocompetent mice. For this purpose, an antibody cross reactive with mouse DLK-1 is site- specifically conjugated using GlycoConnect™ technology to PL1601 , which contains HydraSpace™, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is coadministered with the PD1 inhibitor to mice grafted with a mouse tumour cell line expressing DLK-1. Alternatively, syngeneic models using mouse cell lines genetically engineered to express human DLK1 are used, for treatment with ADCT-701. Typically, the ADC is dosed as a single dose between
0.1 and 1 mg/kg, while the PD1 inhibitor is dosed Q3d x 3 at doses between 1 and 10 mg/kg. Control groups include the ADC or PD1 inhibitor alone. Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group. Statistical analysis (typically a log-rank test) is performed to determine whether the mice treated with the combination have outperformed the mice treated with either ADCT-701 or PD1 inhibitor alone.
Example 6.2: tumours not expressing DLK1
To test whether a PBD-based ADC against DLK1 combined with a PD1 inhibitor shows additive or synergistic effect against tumours not expressing DLK1 , the combination is tested in vivo in a syngeneic tumour model in immunocompetent mice. For this purpose, an antibody cross reactive with mouse DLK-1 is site-specifically conjugated using GlycoConnect™ technology to PL1601 , which contains HydraSpace™, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is co-administered with the PD1 inhibitor to mice grafted with a mouse tumour cell line know to have high levels of infiltrating lymphocytes, such as but not limited to MC38 and CT26. Typically, the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the PD1 inhibitor is dosed Q3d x 3 at doses between 1 and 10 mg/kg. Control groups include the ADC or PD1 inhibitor alone. Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group. Statistical analysis (typically a log-rank test) is performed to determine whether the mice treated with the combination have outperformed the mice treated with either ADC or PD1 inhibitor alone.
Example 7: Prophetic in vivo study of a PBD-based ADC against DLK1 and a PD-L1 antagonist
Example 7.1 : tumours expressing DLK1
To test whether a PBD-based ADC against DLK1 combined with a PDL1 inhibitor shows additive or synergistic effect, the combination is tested in vivo in a syngeneic tumour model in immunocompetent mice. For this purpose, an antibody cross reactive with mouse DLK-1 is site- specifically conjugated using GlycoConnect™ technology to PL1601 , which contains HydraSpace™, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is coadministered with the PDL1 inhibitor to mice grafted with a mouse tumour cell line expressing DLK1 . Alternatively, syngeneic models using mouse cell lines genetically engineered to express human DLK1 are used, for treatment with ADCT-701. Typically, the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the PD1 inhibitor is dosed Q3d x 3 at doses between 1 and 10 mg/kg. Control groups include the ADC or PDL1 inhibitor alone. Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS mice is determined in each group. Statistical analysis (typically a log-rank test) is performed to determine whether the mice treated with the combination have outperformed the mice treated with either ADC or PDL1 inhibitor alone.
Example 7.2: tumours not expressing DLK1
To test whether a PBD-based ADC against DLK1 combined with a PDL1 inhibitor shows additive or synergistic effect against tumours not expressing DLK1 , the combination is tested in vivo in a syngeneic tumour model in immunocompetent mice. For this purpose, an antibody cross reactive with mouse DLK-1 is site-specifically conjugated using GlycoConnect™ technology to PL1601 ,
which contains HydraSpace™, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is co-administered with the PDL1 inhibitor to mice grafted with a mouse tumour cell line know to have high levels of infiltrating lymphocytes, such as but not limited to MC38 and CT26. Typically, the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the PDL1 inhibitor is dosed Q3d x 3 at doses between 1 and 10 mg/kg. Control groups include the ADC or PDL1 inhibitor alone. Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group. Statistical analysis (typically a log-rank test) is performed to determine whether the mice treated with the combination have outperformed the mice treated with either ADC or PDL1 inhibitor alone.
Example 8: Prophetic in vivo study of a PBD-based ADC against DLK1 and a CTLA4 antagonist
Example 8.1 : tumours expressing DLK1
To test whether a PBD-based ADC against DLK1 combined with a CTLA4 inhibitor shows additive or synergistic effect, the combination is tested in vivo in a syngeneic tumour model in immunocompetent mice. For this purpose, an antibody cross reactive with mouse DLK-1 is site- specifically conjugated using GlycoConnect™ technology to PL1601 , which contains HydraSpace™, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is coadministered with the CTLA4 inhibitor to mice grafted with a mouse tumour cell line expressing DLK1. Alternatively, syngeneic models using mouse cell lines genetically engineered to express human DLK1 are used, for treatment with ADCT-701 . Typically, the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the CLTA4 inhibitor is dosed Q3d x 3 at doses between 1 and 10 mg/kg. Control groups include the ADC or CTLA4 inhibitor alone. Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group. Statistical analysis (typically a log-rank test) is performed to determine whether the mice treated with the combination have outperformed the mice treated with either ADC or CTLA4 inhibitor alone.
Example 8.2: tumours not expressing DLK1
To test whether a PBD-based ADC against DLK1 combined with a CTLA4 antagonist shows additive or synergistic effect against tumours not expressing DLK1 , the combination is tested in vivo in a syngeneic tumour model in immunocompetent mice. For this purpose, an antibody cross reactive with mouse DLK-1 is site-specifically conjugated using GlycoConnect™ technology to PL1601 , which contains HydraSpace™, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is co-administered with the CTLA4 antagonist to mice grafted with a mouse tumour cell line know to have high levels of infiltrating lymphocytes, such as but not limited to MC38 and CT26. Typically, the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the CTLA4 antagonist is dosed Q3d x 3 at doses between 1 and 10 mg/kg. Control groups include the ADC or CTLA4 antagonist alone. Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group. Statistical analysis (typically a log- rank test) is performed to determine whether the mice treated with the combination have outperformed the mice treated with either ADC or CTLA4 antagonist alone.
Example 9: Prophetic in vivo study of a PBD-based ADC against DLK1 and an 0X40 agonist
Example 9.1 : tumours expressing DLK1
To test whether a PBD-based ADC against DLK1 combined with a 0X40 agonist shows additive or synergistic effect, the combination is tested in vivo in a syngeneic tumour model in immunocompetent mice. For this purpose, an antibody cross reactive with mouse DLK-1 is site- specifically conjugated using GlycoConnect™ technology to PL1601 , which contains HydraSpace™, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is coadministered with the 0X40 agonist to mice grafted with a mouse tumour cell line expressing DLK1 . Alternatively, syngeneic models using mouse cell lines genetically engineered to express human DLK1 are used, for treatment with ADCT-701. Typically, the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the 0X40 agonist is dosed Q3d x 3 at doses between 1 and 10 mg/kg. Control groups include the ADC or 0X40 agonist alone. Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group. Statistical analysis (typically a log-rank test) is performed to determine whether the mice treated with the combination have outperformed the mice treated with either ADC or 0X40 agonist alone.
Example 9.2: tumours not expressing DLK1
To test whether a PBD-based ADC against DLK1 combined with a 0X40 agonist shows additive or synergistic effect against tumours not expressing DLK1 , the combination is tested in vivo in a syngeneic tumour model in immunocompetent mice. For this purpose, an antibody cross reactive with mouse DLK-1 is site-specifically conjugated using GlycoConnect™ technology to PL1601 , which contains HydraSpace™, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is co-administered with the 0X40 agonist to mice grafted with a mouse tumour cell line know to have high levels of infiltrating lymphocytes, such as but not limited to MC38 and CT26. Typically, the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the 0X40 agonist is dosed Q3d x 3 at doses between 1 and 10 mg/kg. Control groups include the ADC or 0X40 agonist alone. Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group. Statistical analysis (typically a log-rank test) is performed to determine whether the mice treated with the combination have outperformed the mice treated with either ADC or 0X40 agonist alone.
Example 10: Prophetic in vivo study of a PBD-based ADC against DLK1 and a GITR agonist
Example 10.1 : tumours expressing DLK1
To test whether a PBD-based ADC against DLK1 combined with a GITR agonist shows additive or synergistic effect, the combination is tested in vivo in a syngeneic tumour model in immunocompetent mice. For this purpose, an antibody cross reactive with mouse DLK-1 is site- specifically conjugated using GlycoConnect™ technology to PL1601 , which contains HydraSpace™, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is coadministered with the GITR agonist to mice grafted with a mouse tumour cell line expressing DLK1 . Alternatively, syngeneic models using mouse cell lines genetically engineered to express human DLK1 are used, for treatment with ADCT-701. Typically, the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the GITR agonist is dosed Q3d x 3 at doses between 1 and 10 mg/kg. Control groups include the ADC or GITR agonist alone. Tumour volumes and body weight is
subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group. Statistical analysis (typically a log-rank test) is performed to determine whether the mice treated with the combination have outperformed the mice treated with either ADC or GITR agonist alone. Example 10.2: tumours not expressing DLK1
To test whether a PBD-based ADC against DLK1 combined with a GITR agonist shows additive or synergistic effect against tumours not expressing DLK1 , the combination is tested in vivo in a syngeneic tumour model in immunocompetent mice. For this purpose, an antibody cross reactive with mouse DLK-1 is site-specifically conjugated using GlycoConnect™ technology to PL1601 , which contains HydraSpace™, a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199, and this ADC is co-administered with the GITR agonist to mice grafted with a mouse tumour cell line know to have high levels of infiltrating lymphocytes, such as but not limited to MC38 and CT26. Typically, the ADC is dosed as a single dose between 0.1 and 1 mg/kg, while the GITR agonist is dosed Q3d x 3 at doses between 1 and 10 mg/kg. Control groups include the ADC or GITR agonist alone. Tumour volumes and body weight is subsequently measured up to 60 days for all groups and the number of partially responding (PR), completely responding (CR) tumour free surviving (TFS) mice is determined in each group. Statistical analysis (typically a log-rank test) is performed to determine whether the mice treated with the combination have outperformed the mice treated with either ADC or GITR agonist alone.
Claims
1 . ADCT-701 for use in a method for treating a disorder in an individual, the method comprising administering to the individual an effective amount of ADCT-701 and a secondary agent selected from gemcitabine a PARP inhibitor and a checkpoint modulator.
2. ADCT-701 for use according to claim 1 , wherein the individual has, or has been determined to have, a cancer which expresses DLK1 or DLK1+ve tumour-associated non-tumour cells, such as DLK1+ve infiltrating cells.
3 ADCT-701 for use according to claim 1 or claim 2, wherein the individual is undergoing treatment with the secondary agent.
4. ADCT-701 for use according to any one of the previous claims, wherein the individual has undergone treatment with the secondary agent.
5. ADCT-701 for use according to any one of the previous claims, wherein the individual is refractory to treatment, or further treatment, with the secondary agent.
6. ADCT-701 for use according to any one of the previous claims, wherein the disorder is a proliferative disease, such as cancer.
7. ADCT-701 for use according to claim 6, wherein the disorder is selected from the group comprising: hepatocellular carcinoma, hepatoblastoma, lung cancer, non small cell lung cancer, small cell lung cancer, breast cancer, gastric cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carcinoma, ovarian cancer, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, hepatocellular carcinoma, rhabdomyosarcoma, cholangiacarcinoma, kidney cancer, renal cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi’s sarcoma, melanoma, neuroblastoma, adrenal gland cancer, adrenocortical carcinoma, pheochromocytoma, paraganglioma, thyroid medullary cancer, thyroid medullary carcinoma, skeletal muscle cancer, liposarcoma, bone-derived cancer glioma, Wilms tumour, neuroendocrine tumours, Acute Myeloid Leukaemia or Myelodysplastic syndrome.
8. ADCT-701 for use according to any one of the previous claims wherein the secondary agent is gemcitabine.
9. ADCT-701 for use according to any one of claims 1 to 8 wherein the secondary agent is a checkpoint modulator selected from the group consisting of: a PD-1 antagonist, a PD-L1 antagonist, a CTLA-4 antagonist, an 0X40 agonist, or a GITR agonist, such an agent selected from Nivolumab, Pembrolizumab, Cemiplimab, Atezolizumab, Durvalumab, Avelumab or Ipilimumab.
10. ADCT-701 for use according to any one of claims 1 to 8 wherein the secondary agent is a PARP inhibitor selected from the group consisting of: Olaparib, CEP-9722, Talazoparib, Rucaparib, Iniparib, Veliparib, Niraparib, Pamiparib, 3-Aminobenzamide, or E7016.
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