WO2024249596A2 - Méthodes de traitement de cancers liés à l'igf-1r avec un ligand du récepteur du facteur de croissance insulinique 1 conjugué à un agent cytotoxique - Google Patents

Méthodes de traitement de cancers liés à l'igf-1r avec un ligand du récepteur du facteur de croissance insulinique 1 conjugué à un agent cytotoxique Download PDF

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WO2024249596A2
WO2024249596A2 PCT/US2024/031615 US2024031615W WO2024249596A2 WO 2024249596 A2 WO2024249596 A2 WO 2024249596A2 US 2024031615 W US2024031615 W US 2024031615W WO 2024249596 A2 WO2024249596 A2 WO 2024249596A2
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igf
cancer
seq
wildtype
ligand
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WO2024249596A3 (fr
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Matthew HOBERMAN
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Lirum Therapeutics Inc
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Lirum Therapeutics Inc
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Priority to CN202480047411.8A priority patent/CN121586579A/zh
Priority to KR1020257043392A priority patent/KR20260020410A/ko
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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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/642—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the peptide or protein in the drug conjugate being a cytokine, e.g. IL2, chemokine, growth factors or interferons being the inactive part of the conjugate
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A61K38/1754—Insulin-like growth factor binding proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • FIELD The presently disclosed subject matter relates generally to methods of treating cancers in particular by administering an IGF-1R ligand conjugated to a cytotoxic agent.
  • REFERENCE TO A SEQUENCE LISTING [003] The Sequence Listing written in file name 614073SEQLIST.xml is 16.7 kilobytes, was created on May 23, 2024, and is hereby incorporated by reference.
  • BACKGROUND [004]
  • IGF-1R insulin-like growth factor-1 receptor
  • IGF-1 insulin-like growth factor-1 receptor
  • IGF-1 insulin growth factor-1
  • IGF-1 insulin growth factor-1
  • IGF-1 is secreted by the liver into the circulatory system and stimulates growth of many cell types. IGF-1 is also produced by many cell types throughout the body, including many cancers, for autocrine and paracrine effects. IGF-1 production is stimulated by growth hormone. (Stewart, C. H., et al., 1996, Physiol. Revs.76:1005; Yakar, S., et al., 2002, Endocrine 19:239).
  • IGF-1R is often found to be expressed at higher levels in cancer cells of adults than in normal cells of the same tissue type. Increased IGF-1R activity promotes cancer cell proliferation, migration, and invasion and is associated with tumor metastasis, treatment resistance, poor prognosis, and shortened survival in patients with cancer. Further, epidemiological studies have reported a positive association between circulating IGF ⁇ 1 levels and various primary cancers, such as breast, colorectal, and prostate cancer.
  • IGF ⁇ Attorney Docket No.074530/614073 1 are associated with an increased risk of tumors including prostate, pre ⁇ and postmenopausal breast, lung, thyroid, and colorectal cancers (Ma et al., 1999; Renehan et al., 2004; Shi et al., 2001).
  • IGF-1R related-cancers There is currently a need for treatments against IGF-1R related-cancers. The subject matter described herein addresses this need.
  • the subject matter described herein is directed to methods for treating an insulin-like growth factor 1 receptor (IGF-1R)-related cancer in a subject, the method comprising administering to the subject a conjugate comprising an IGF-1R ligand, or portion or variant thereof, and a cytotoxic agent.
  • IGF-1R insulin-like growth factor 1 receptor
  • the subject matter described herein is directed to methods for treating an IGF-1R-related cancer in a subject, the method comprising administering to the subject a conjugate comprising an IGF-1R ligand, or portion or variant thereof, and a cytotoxic agent, wherein the IGF-1R-related cancer is selected from the group consisting of head and neck cancer, triple negative breast cancer, bladder cancer, gastrointestinal stromal tumor, adenoid cystic carcinoma, lung cancer, colorectal cancer, prostate cancer, pancreatic cancer, liver cancer, esophageal cancer, ovarian cancer, kidney cancer and stomach cancer.
  • the subject matter described herein is directed to methods for treating an IGF-1R-related cancer in a subject, the method comprising administering to the subject a conjugate comprising an IGF-1R ligand, or portion or variant thereof, and a cytotoxic agent, wherein the IGF-1R-related cancer is selected from the group consisting of head and neck cancer, triple negative breast cancer, bladder cancer, gastrointestinal stromal tumor and adenoid cystic carcinoma.
  • the subject matter described herein is directed to methods for treating an IGF-1R-related cancer in a subject, the method comprising administering to the subject a conjugate comprising an IGF-1R ligand, or portion or variant thereof, and a cytotoxic agent, wherein the IGF-1R ligand, or portion or variant thereof comprises wildtype insulin-like growth factor 1 (IGF-1) (SEQ ID NO:3), wildtype insulin (SEQ ID NO:10 and SEQ ID NO:11), wildtype insulin-like growth factor 2 (IGF-2) (SEQ ID NO:12), a variant of wildtype IGF-1 (SEQ ID NO:3), a variant of wildtype insulin (SEQ ID NO:10 and SEQ ID NO:11), or a variant of wildtype IGF-2 (SEQ ID NO:12).
  • IGF-1R ligand, or portion or variant thereof comprises wildtype insulin-like growth factor 1 (IGF-1) (SEQ ID NO:3), wildtype insulin (SEQ ID NO:10 and SEQ ID NO:11), wildtype
  • the subject matter described herein is directed to methods for treating an IGF-1R-related cancer in a subject, the method comprising administering to the subject a conjugate comprising an IGF-1R ligand, or portion or variant thereof, and a cytotoxic agent, wherein the IGF-1R ligand, or portion or variant thereof comprises a variant of wildtype insulin-like growth factor 1 (IGF-1) (SEQ ID NO:3).
  • IGF-1R ligand, or portion or variant thereof comprises a variant of wildtype insulin-like growth factor 1 (IGF-1) (SEQ ID NO:3).
  • the subject matter described herein is directed to methods for treating an IGF-1R-related cancer in a subject, the method comprising administering to the subject a conjugate comprising an IGF-1R ligand, or portion or variant thereof, and a cytotoxic agent, wherein the IGF-1R ligand, or portion or variant thereof comprises SEQ ID NO:2.
  • the subject matter described herein is directed to methods for treating an IGF-1R-related cancer in a subject, the method comprising administering to the subject a conjugate comprising an IGF-1R ligand, or portion or variant thereof, and a cytotoxic agent, wherein the cytotoxic agent is a chemotherapeutic agent.
  • the subject matter described herein is directed to methods for treating an IGF-1R-related cancer in a subject, the method comprising administering to the subject a conjugate comprising an IGF-1R ligand, or portion or variant thereof, and a cytotoxic agent, wherein the cytotoxic agent is methotrexate.
  • the subject matter described herein is directed to methods for treating an IGF-1R-related cancer in a subject, the method comprising administering to the subject a conjugate comprising an IGF-1R ligand, or portion or variant thereof, and a cytotoxic agent, wherein the cytotoxic agent comprises a toxin.
  • the subject matter described herein is directed to methods for treating an IGF-1R-related cancer in a subject, the method comprising administering to the subject a conjugate comprising an IGF-1R ligand, or portion or variant thereof, and a cytotoxic agent, wherein the cytotoxic agent comprises Clostridium perfringens enterotoxin, diphtheria toxin, ricin chain A, Pseudomonas exotoxin, A chain toxins, a ribosome inactivating protein, ⁇ -sarcin, aspergillin, or a ribonuclease.
  • the subject matter described herein is directed to methods for treating an IGF-1R-related cancer in a subject, the method comprising administering to the subject a conjugate comprising an IGF-1R ligand, or portion or variant thereof, and a cytotoxic agent, wherein the IGF-1R ligand, or portion or variant thereof comprises SEQ ID NO:2, the cytotoxic Attorney Docket No.074530/614073 agent is methotrexate, wherein the methotrexate is covalently bound to a lysine of SEQ ID NO:2, and the IGF-1R-related cancer is selected from the group consisting of head and neck cancer, triple negative breast cancer, bladder cancer, gastrointestinal stromal tumor, adenoid cystic carcinoma, lung cancer, colorectal cancer, prostate cancer, pancreatic cancer, liver cancer, esophageal cancer, ovarian cancer, kidney cancer and stomach cancer.
  • Figures 1A&C depict dose-response curves and IC50s for a conjugate described herein against head and neck cancer cell lines, FaDU (A) and SCC-25 (C).
  • Figures 1B&D depict IGF- 1R expression levels in FaDU (B) and SCC-25 (D).
  • Figures 2A&C depict dose-response curves and IC50s for a conjugate described herein against triple negative breast cancer cell lines, BT-20 (A) and HCC1143 (C).
  • Figures 2B&D depict IGF-1R expression levels in BT-20 (B) and HCC1143 (D).
  • Figures 3A&C depict dose-response curves and IC50s for a conjugate described herein against bladder cancer cell lines, 5637 (A) and T-24 (C).
  • Figures 3B&D depict IGF-1R expression levels in 5637 (B) and T-24 (D).
  • Figures 4A-C depict dose-response curves and IC 50 s for a conjugate described herein against lung cancer cell lines, A549 (A), NCI-H2122 (B), and NCI-H526 (C).
  • Figures 5A-D depict dose-response curves and IC 50 s for a conjugate described herein against colorectal cancer cell lines, COLO 205 (A) and HT-29 (B), and prostate cancer cell lines, VCaP (C) and DU 145 (D).
  • Figures 6A-D dose-response curves and IC 50 s for a conjugate described herein against pancreatic cancer cell lines, Capan-2 (A) and PANC-1 (B), and liver cancer cell lines, Hep G2 (C) and Huh-7 (D).
  • IGF-1R insulin-like growth factor 1 receptor
  • a targeted therapy directed to IGF-1R that comprises an IGF-1 or variant thereof in combination with a cytotoxic payload.
  • a particular conjugate known as LX-101 was well-tolerated and demonstrated single agent activity in previous Phase 1 trials of adult patients with advanced, pretreated cancers.
  • Disclosed herein are studies that show a conjugate has potent anti-tumor activity against a variety of cancer cell lines related to IGF-1R, further supporting the clinical development of the methods described herein to address the unmet needs in treating cancers, including head and neck cancer, triple negative breast cancer, bladder cancer, gastrointestinal stromal tumor and adenoid cystic carcinoma.
  • a patient or subject and the like is any mammal suffering from an IGF-1R- related cancer.
  • the term “mammal” includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep. In certain embodiments, the patient or subject is human adult or child.
  • the methods involve treating a human subject about or under the age of 21 years at the time of diagnosis or treatment (i.e., a pediatric subject).
  • the term “pediatric” can be further divided into various subpopulations including: neonates (from birth through the first 28 days of life); infants (29 days of age to less than two years of age); children (two years of age to less than 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)).
  • the term “conjugate” refers to a molecule comprising an IGF-1R ligand, or portion or variant thereof, and a cytotoxic agent.
  • IGF-1R insulin-like growth factor 1 receptor
  • cytotoxic agent refers to any agent capable of preventing, delaying, reducing and/or reversing the activity, severity, and/or progression of the disease when treated in accordance with the methods described herein.
  • cytotoxic agent that results in cell killing
  • the term “residue” or “residue of” a chemical moiety or compound refers to a chemical moiety or compound that is bound to a molecule, whereby through the binding, at least one covalent bond has replaced at least one atom of the original chemical moiety or compound, resulting in a residue of the chemical moiety or compound in the molecule.
  • a subject is “refractory” to prior treatment if the subject has failed to achieve a response to a therapy such that the therapy is determined to not be therapeutically effective, such as: failure to reach clinical endpoint, including any of response, extended duration of response, extended disease-free survival, relapse-free survival, and progression-free survival.
  • Attorney Docket No.074530/614073 [036]
  • “and/or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).
  • the subject matter described herein is directed to a method for treating an insulin-like growth factor 1 receptor (IGF-1R)-related cancer in a subject, said method comprising administering to the subject a conjugate comprising an IGF-1R ligand, or portion or variant thereof, and a cytotoxic agent.
  • IGF-1R insulin-like growth factor 1 receptor
  • the patient is an adult patient, over about 21 years of age.
  • the subject is a pediatric subject under about 21 years of age.
  • the patient is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age to 21 years of age (up to, but not including, the twenty-first birthday).
  • the Attorney Docket No.074530/614073 patient is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 21 years of age.
  • the methods treat a subject in need thereof, which can further include performing a morphological diagnosis prior to administering the conjugate.
  • the methods can further include performing molecular testing prior to administering the conjugate.
  • the method includes performing morphological diagnosis and molecular testing prior to administering the conjugate.
  • IGF-1R is overexpressed in tumor cells of the IGF-1R-related cancer.
  • the IGF-1R is overexpressed on tumor cells relative to non-tumor cells.
  • the overexpression of IGF-1R on tumor cells of said IGF-1R-related cancer confers poor prognosis.
  • the overexpression of IGF-1R on tumor cells is measured by flow cytometry or immunohistochemistry.
  • the IGF-1R-related cancer has one or more genetic alterations that activate the IGF-1R signaling pathway.
  • the genetic alteration is a mutation, gene fusion, gene amplification, or translocation.
  • the IGF-1R-related cancer is selected from the group consisting of head and neck cancer, triple negative breast cancer, bladder cancer, gastrointestinal stromal tumor, adenoid cystic carcinoma, lung cancer, colorectal cancer, prostate cancer, pancreatic cancer, liver cancer, esophageal cancer, ovarian cancer, kidney cancer and stomach cancer.
  • the IGF-1R-related cancer is selected from the group consisting of head and neck cancer, triple negative breast cancer, bladder cancer, gastrointestinal stromal tumor and adenoid cystic carcinoma. In certain embodiments, the IGF-1R-related cancer is selected from the group consisting of head and neck cancer, triple negative breast cancer and bladder cancer. [047] In some embodiments, the IGF-1R-involved cancer is head and neck cancer, or squamous cell carcinomas of the head and neck region (HNSCC). HNSCCs are categorized by the presence or absence of HPV.
  • HNSCC Patients with HNSCC that is associated with HPV, or HPV(+), are generally Attorney Docket No.074530/614073 younger, have better responses to chemotherapy and radiation, and have an overall better prognosis than patients with HPV(-) disease. Of the approximately 50,000 patients diagnosed with HNSCC in the United States each year, an estimated 30% have HPV(-) disease.
  • Treatment for HPV(-) HNSCC includes chemotherapy, radiation therapy, and surgery.
  • the systemic therapies most often used include pembrolizumab, 5-FU, and nivolumab. These treatments have historically led to a 5- year overall survival rate of 45% for HPV(-) cases, compared to ⁇ 80% for disease associated with HPV(+).
  • the IGF-1R-involved cancer is muscle-invasive bladder cancer. Approximately 80,000 new cases of bladder cancer are diagnosed in the United States annually. These cancers range from non-invasive, slow-progressing tumors to highly aggressive, rapidly proliferating malignancies. One of the key defining characteristics of bladder cancer is whether or not the tumor has invaded the muscle around the bladder.
  • Non-muscle-invasive bladder cancer Cancer that has stayed within the muscle walls of the bladder is considered non-muscle-invasive bladder cancer. These patients account for approximately 70% of cases and respond well to current treatment options, although recurrence is common (literature shows anywhere from 30-65%). The other 30% of cases are cancers where the tumor has invaded the muscle around the bladder or metastasized beyond the muscle, which is referred to as muscle-invasive bladder cancer. Muscle-invasive bladder cancer patients historically have a poorer response to available therapies and worse outcomes. Standard of care for muscle- invasive bladder cancer is currently multi-modal chemotherapy followed by surgery. This treatment regimen has proven inadequate, as 5-year overall survival rates, even with successful surgery, are still as low as 40% for these patients.
  • muscle-invasive bladder cancer does have many other treatment options targeting various potential weaknesses in the malignancy with varying success.
  • many of the recent regulatory approvals in muscle-invasive bladder cancer have been based on single-arm, nonrandomized studies with overall response rates end points.
  • the IGF-1R-involved cancer is triple negative breast cancer.
  • Triple negative breast cancer is a type of breast cancer that has no or little expression of estrogen receptor, progesterone, and human epidermal growth factor receptor-2.
  • patients with triple negative breast cancer have more aggressive disease, limited treatment options and a higher frequency of recurrence and metastases, leading to poorer outcomes and inferior survival rates.
  • Approximately 15-20% of all breast cancers are triple negative, amounting to an incidence of around 45,000 patients per year in the United States.
  • the IGF-1R-involved cancer is gastrointestinal stromal tumors.
  • Gastrointestinal stromal tumors are mesenchymal neoplasms derived from the gastrointestinal system. Approximately 6,000 patients are diagnosed with gastrointestinal stromal tumors per year, with 90% of patients harboring a gain of function mutation in either the KIT or PDGFRA proto- oncogenes. The remaining 10% of patients that do not have either of these mutations are considered to have wildtype disease and consist almost entirely of pediatric patients.
  • the IGF-1R-involved cancer is adenoid cystic carcinoma.
  • Adenoid cystic carcinoma is a malignancy mainly of the secretory glands.
  • Adenoid cystic carcinoma is driven by a genetic translocation resulting in the MYB-NFIB fusion protein. Almost 1,700 patients are diagnosed with adenoid cystic carcinoma every year in the United States, with 5- and 16-year prevalence pools of 5,000 and 10,500 patients, respectively. Due to the slow but relentless progression of the disease, tumor recurrence is the biggest challenge with the limited currently available therapies. This is evinced by the decline of overall survival rates. Five, ten, and fifteen- year overall survival rates for adenoid cystic carcinoma are 60%, 50%, and 29%, respectively, due to the high incidence of metastases and recurrence. Currently, the standard of care for adenoid cystic carcinoma is surgery, sometimes combined with radiation therapy.
  • the IGF-1R-involved cancer is lung cancer, colorectal cancer, prostate cancer, ovarian cancer, gastric cancer, liver cancer, pancreatic cancer, kidney cancer, or esophageal cancer.
  • the conjugate can comprise a conjugate in which the IGF-1R ligand and the cytotoxic agent are chemically linked together, either directly or through a chemical linker.
  • the conjugate is a genetic recombinant in which the conjugate is expressed as a single polypeptide.
  • the translated conjugate preferably comprises a toxin, or portion or variant thereof, linked via a peptide bond to the IGF-1R ligand.
  • the conjugate is a fusion protein described in U.S. Patent No.9,675,671, which is hereby incorporated by reference in its entirety.
  • the nucleotide sequences encoding the IGF-1R ligands can be produced by standard recombinant DNA techniques or by protein synthetic techniques, cloned into an appropriate expression vector using standard molecular biology techniques, expressed in bacterial, insect, or mammalian cells, and purified by any method known in the art for purification of a protein.
  • Conjugates described herein Attorney Docket No.074530/614073 comprising an IGF-1R ligand and a chemotherapeutic agent can be made by standard chemistry and protein conjugation techniques and are described in U.S. Patent No. 7,811,982; U.S. Patent No. 9,675,671; and U.S. Patent No.
  • IGF-1R is a heterotetramer consisting of two extracellular ligand-binding a subunits and two transmembrane b subunits with kinase activity that mediate signal transduction.
  • the native ligands to the IGF-1R are IGF-1, IGF-2, and insulin.
  • the IGF-1R has the highest affinity for IGF- 1, followed by IGF-2, and can bind to insulin with 50- to 100-fold lower affinity. IGF-1R can also form hybrid receptors by dimerization with the insulin receptor. See Hakuno et al. J Mol Endocrinol.61(1):T69-T86 (2016).
  • the IGF-1R ligand in the conjugate comprises wildtype IGF-1 (SEQ ID NO:3), wildtype insulin (SEQ ID NO:10 and SEQ ID NO:11; mature insulin consists of two chains connected by disulfide bonds, chain A, corresponding to SEQ ID NO:10, and chain B, corresponding to SEQ ID NO:11, hence the recitation of two SEQ ID NOs), or wildtype IGF-2 (SEQ ID NO:12).
  • the IGF-1R ligand in the conjugate comprises a variant of wildtype IGF-1 (SEQ ID NO:3), a variant of wildtype insulin (SEQ ID NO:10 and SEQ ID NO:11), or a variant of wildtype IGF-2 (SEQ ID NO:12).
  • the variant of wildtype IGF-1 is at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to IGF-1 (SEQ ID NO:3)
  • said variant of wildtype insulin is at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to insulin (SEQ ID NO:10 and SEQ ID NO:11)
  • said variant of wildtype IGF-2 is at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical to IGF-2 (SEQ ID NO:12).
  • the IGF-1R ligand in the conjugate comprises a variant of IGF-1 that has reduced binding affinity for IGFBPs as compared to wildtype IGF-1 (SEQ ID NO:3) or a variant of IGF-2 that has reduced binding affinity for IGFBPs as compared to wildtype IGF-2 (SEQ ID NO:12).
  • IGFBPs belong to a family of at least six proteins that bind to IGF-1 and IGF-2 with high affinity. IGFBPs bind to the majority of IGFs in circulation, increasing their half-life, regulating their bioavailability, and generally inhibit their ability to bind to the IGF receptors.
  • IGF-1 variants with reduced binding affinity for IGFBPs are known in the art and include IGF132 (disclosed in U.S.
  • Patent No.4,876,242 in which the first 17 amino acids of the B chain of insulin (SEQ ID NO:11) replace the first 16 amino acids of human IGF-1 (SEQ ID NO:3); R3- IGF-1 (SEQ ID NO:6), in which glutamic acid in position 3 of the native human IGF-1 (SEQ ID NO:3) is substituted by arginine; and des(1-3)IGF-1 (SEQ ID NO:7), which lacks the first three amino acids of human IGF-1 (SEQ ID NO:3).
  • R3-IGF-1 and des(1-3)IGF-1 are described in Francis et al., J Mol Endocrinol. 8(3):213-23 (1992).
  • the conjugate comprises IGF132 (SEQ ID NO:4), R3-IGF-1 (SEQ ID NO:6), or des(1-3)-IGF-1 (SEQ ID NO:7).
  • the variant of IGF-1 has higher affinity for the IGF-1R than wildtype IGF-1 (SEQ ID NO:3), or the variant of IGF-2 has higher affinity for the IGF-1R than wildtype IGF-2 (SEQ ID NO:12).
  • the IGF-1R ligand in the conjugate comprises 765IGF (SEQ ID NO:2), long-R3-IGF-1 (SEQ ID NO:5), long-IGF-1 (SEQ ID NO:8), or long-G3-IGF-1 (SEQ ID NO:9).
  • 765IGF, long-R3-IGF-1, long-IGF-1, and long-G3-IGF-1 have N-terminal leader sequences that facilitate protein purification and provide sites for conjugation of cytotoxic agents, as described above.
  • 765IGF (SEQ ID NO:2) comprises SEQ ID NO:1 followed by R3-IGF-1 (SEQ ID NO:6); long-R3-IGF-1 (SEQ ID NO:5) comprises the first 11 amino acids of methionyl porcine growth hormone, followed by a Val-Asn dipeptide, followed by R3-IGF-1 (SEQ ID NO:6); long- IGF-1 (SEQ ID NO:8) comprises the first 11 amino acids of methionyl porcine growth hormone, followed by a Val-Asn dipeptide, followed by human IGF-1 (SEQ ID NO:3); and long-G3-IGF-1 comprises the first 11 amino acids of methionyl porcine growth hormone, followed by a Val-Asn dipeptide, followed by a
  • the IGF-1R ligand comprises wildtype insulin-like growth factor 1, wildtype insulin, or wildtype insulin-like growth factor 2 (IGF-2).
  • the wildtype insulin-like growth factor 1 comprises SEQ ID NO:3, wherein said wildtype insulin comprises SEQ ID NO:10 or 11, and wherein said wildtype insulin-like growth factor 2 (IGF-2) comprises SEQ ID NO:12.
  • Attorney Docket No.074530/614073 [062]
  • the IGF-1R ligand comprises a variant of wildtype IGF-1, a variant of wildtype insulin, or a variant of wildtype IGF-2.
  • the variant of wildtype IGF- 1 is at least 90% identical to SEQ ID NO:3
  • said variant of wildtype insulin is at least 90% identical to SEQ ID NO:10 or 11
  • said variant of wildtype IGF-2 is at least 90% identical to SEQ ID NO:12.12.
  • the variant of wildtype IGF-1 has reduced binding affinity for insulin-like growth factor binding proteins (IGFBPs) as compared to wildtype IGF-1, or the variant of wildtype IGF-2 has reduced binding affinity for IGFBPs as compared to wildtype IGF-2, and/or (ii) the variant of wildtype IGF-1 has increased affinity for the IGF-1R as compared to wildtype IGF-1, or the variant of wildtype IGF-2 has increased affinity for the IGF-1R as compared to wildtype IGF-2.
  • the IGF-1R ligand, or portion or variant thereof comprises a leader sequence.
  • the leader sequence comprises SEQ ID NO:1.
  • the IGF-1R ligand comprises 765IGF (SEQ ID NO:2), IGF-132 (SEQ ID NO:4), long-R3-IGF-1 (SEQ ID NO:5), R3-IGF-1 (SEQ ID NO:6), des(1-3)-IGF-1 (SEQ ID NO:7), long-IGF-1 (SEQ ID NO:8), or long-G3-IGF-1 (SEQ ID NO:9).
  • the IGF-1R ligand comprises 765IGF (SEQ ID NO:2).
  • the IGF-1R ligand, or portion or variant thereof, is covalently bound to the cytotoxic agent.
  • the cytotoxic agent comprises a chemotherapeutic agent.
  • the chemotherapeutic agent is amsacrine, azacytidine, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytarabine, dactinomycin, daunorubicin, decarbazine, docetaxel, doxorubicin, epirubicin, estramustine, etoposide, floxuridine, fludarabine, fluorouracil, gemcitabine, hexamethylmelamine, idarubicin, ifosfamide, irinotecan, lomustine, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitomycin C, mitotane, mitoxantrone, oxalip
  • the chemotherapeutic agent is methotrexate. In certain aspects, the chemotherapeutic agent is covalently bound to a lysine residue in the leader sequence. In certain aspects, the chemotherapeutic agent is one or more methotrexate residues covalently bound to any available lysine residue in the leader sequence.
  • Attorney Docket No.074530/614073 [068]
  • a conjugate comprises more than one cytotoxic agent bound to the IGF-1R ligand. In certain aspects, the conjugate can comprise one to 12 cytotoxic agents, or 6 to 10 cytotoxic agents, or about 8 cytotoxic agents.
  • the conjugate can comprise one to twelve covalently bound cytotoxic agents, or 6 to 10 covalently bound cytotoxic agents, or about 8 covalently bound cytotoxic agents.
  • the chemotherapeutic agent(s) are covalently bound to any available position on the IGF-1R ligand.
  • the chemotherapeutic agent(s) are covalently bound to any available lysine residue.
  • the chemotherapeutic agent(s) are covalently bound to any available lysine in the leader sequence when present.
  • Leader sequences can incorporate tags, such as polyhistidine tags, to facilitate protein purification, as well as provide sites for conjugation of cytotoxic agents.
  • the leader sequence comprises SEQ ID NO:1.
  • the cytotoxic agent comprises a toxin.
  • the toxin comprises Clostridium perfringens enterotoxin, diphtheria toxin, ricin chain A, Pseudomonas exotoxin, A chain toxins, a ribosome inactivating protein, ⁇ -sarcin, aspergillin, or a ribonuclease.
  • the toxin comprises Clostridium perfringens enterotoxin, or a portion or variant thereof.
  • the toxin comprises SEQ ID NO:14 or SEQ ID NO:15.
  • the toxin comprises diphtheria toxin, or a portion or variant thereof. In certain aspects, the toxin comprises SEQ ID NO:13 or SEQ ID NO:16.
  • the subject matter described herein is directed to methods for treating an IGF-1R-related cancer in a subject, the method comprising administering to the subject a conjugate comprising an IGF-1R ligand, or portion or variant thereof, and a cytotoxic agent, wherein the IGF-1R ligand, or portion or variant thereof comprises SEQ ID NO:2, the cytotoxic agent is methotrexate, wherein the methotrexate is covalently bound to a lysine of SEQ ID NO:2, and the IGF-1R-related cancer is selected from the group consisting of head and neck cancer, triple negative breast cancer, and bladder cancer.
  • the conjugate is LX-101 (a conjugate as described above wherein the IGF-1R ligand is SEQ ID NO:2, the cytotoxic agent is methotrexate, and wherein at least 6 and up to 10, or at least 6 and up to 9, or at least 7 and up to 9, or at least 8 and up to 9 methotrexate are present for every IGF-1R ligand.
  • a methotrexate can be covalently bound to the IGF-1R ligand, in particular, a lysine residue of SEQ ID NO:2. The average number of methotrexate residues per SEQ ID NO:2 is 8).
  • the subject matter described herein is directed to methods for treating an IGF-1R- related cancer in a subject, the method comprising administering LX-101 to the subject, wherein the IGF-1R-related cancer is head and neck cancer. In certain embodiments, the subject matter described herein is directed to methods for treating an IGF-1R-related cancer in a subject, the method comprising administering LX-101 to the subject, wherein the IGF-1R-related cancer is triple negative breast cancer. In certain embodiments, the subject matter described herein is directed to methods for treating an IGF-1R-related cancer in a subject, the method comprising administering LX-101 to the subject, wherein the IGF-1R-related cancer is bladder cancer.
  • the number of methotrexate residues per conjugate is 6, 7, 8, 9 or 10. In all embodiments, the average number of methotrexate residues per conjugate in a composition is 6, 7, 8, 9 or 10. [072] In certain embodiments, the subject (i) has not previously received treatment for the IGF- 1R-related cancer; (ii) has previously received treatment for the IGF-1R-related cancer; (iii) has relapsed from previous treatment for the IGF-1R-related cancer; (iv) was refractory to previous treatment for the IGF-1R-related cancer; or (v) is susceptible to adverse reactions from other treatments for the IGF-1R-related cancer.
  • the IGF-1R-related cancer is recurrent where the patient has relapsed after a previous treatment.
  • the IGF-1R-related cancer is Stage II, III or IV.
  • the IGF- 1R-related cancer has progressed to Stage II, III or IV during or after an initial therapy.
  • the treatment results in a reduction in the growth of tumor cells in the subject.
  • the reduction is caused by killing of IGF-1R-expressing tumor cells.
  • Table 1 provides a listing of sequences referenced herein. Table 1.
  • Table 1 Description of the Sequences D Attorney Docket No.074530/614073 IGF132 FVNQHLCGSHLVEALYLVCGDRGFYFNKPTGYGSSSRR 4 APQTGIVDECCFRSCDLRRLEMYCAPLKPAKSA Attorney Docket No.074530/614073 enterotoxin – EQNTIERSVSTTAGPNEYVYYKVYATYRKYQAIRISHGN long-R3-IGF-1 ISDDGSIYKLTGIWLSKTSADSLGNIDQGSLIETGERCVLT [ ] n certa n em o ments, t e met o s escr e ere n are part o a com nat on t erapy.
  • the methods described herein can be used either alone or in combination with standard of care treatment options for each type of cancer.
  • the standard of care options include surgery, systemic chemotherapy (either pre- or post-operatively) and/or radiation therapy.
  • the subject having an IGF-1R-related cancer treated in accordance with the methods described herein has not previously received treatment for the IGF-1R-related cancer.
  • the subject having an IGF-1R-related cancer treated in accordance with the methods described herein has previously received treatment for the IGF-1R-related cancer.
  • the subject has relapsed from previous treatment for the IGF-1R- related cancer.
  • the subject was refractory to previous treatment for the IGF-1R- related cancer.
  • the conjugate is administered at a dose and frequency that is appropriate for the subject and the IGF-1R-related cancer being treated at the discretion of the practitioner.
  • the conjugate is administered at a dose of about 0.05, 0.10, 0.20, 0.40, 0.80, 1.0, 1.5, 1.6, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10.0 ⁇ Eq/kg of body weight or at a dose range of about 0.05-10.0, 0.1-8.0, 0.2-4.0, 0.3-3, 0.4-2.5, 0.05- 0.5, 0.5-1.0, 1.0-1.5, 1.5-2.0, 2.0-2.5, 2.5-3.0, 3.0-3.5, 3.5-4.0, 4.0-4.5, 4.5-5.0, 5.0-5.5, 5.5-6.0, 6.0-6.5, 6.5-7.0, 7.0-7.5, 7.5-8.0, 8.0-8.5, 8.5-9.0, 9.0-9.5, or 9.5-10.0 ⁇ Eq/kg of body weight.
  • the conjugate is administered at a dose of about 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2
  • the conjugate is administered daily, every other day, every three days, every four days, every five days, every six days, once per week, once every two weeks, once every three weeks, once every four weeks, once per month, every two months, or every three months.
  • the conjugate can be administered at a lower dose and/or frequency at which the cytotoxic agent would have an effect when dosed as a single agent.
  • the conjugate is dosed at the maximum tolerated dose (MTD). “MTD,” as used herein, refers to the highest dose of an agent that an individual patient can tolerate Attorney Docket No.074530/614073 as determined by the practitioner.
  • the methods do not cause appreciable or unacceptable hyperglycemia in the subject. In certain aspects, the methods do not cause unacceptable hyperglycemia in the subject.
  • Hyperglycemia is another term for high blood glucose and can occur when there is insufficient insulin in the body or when the body cannot utilize insulin properly. Unacceptable hyperglycemia refers to an adverse effect of grade 3 or higher, as determined by a treating physician, and/or one that cannot be controlled with diabetic medications and leads to discontinuation of treatment with the conjugate.
  • the methods do not cause appreciable or unacceptable hyperglycemia in the subject.
  • the methods do not cause unacceptable hyperglycemia in the subject.
  • Hyperglycemia is another term for high blood glucose and can occur when there is insufficient insulin in the body or when the body cannot utilize insulin properly.
  • Unacceptable hyperglycemia refers to an adverse effect of grade 3 or higher, as determined by a treating physician, and/or one that cannot be controlled with diabetic medications and leads to discontinuation of treatment with the conjugate.
  • the conjugates described herein can be formulated in pharmaceutical compositions for use in the methods described herein.
  • the pharmaceutical composition comprises an effective amount of a conjugate and a pharmaceutically acceptable carrier or vehicle.
  • Such pharmaceutical compositions can be formulated to be suitable for administration to a subject and can be in any form that allows for the composition to be administered to a subject.
  • Materials used in preparing the pharmaceutical compositions can be non-toxic in the amounts used. It will be evident to those of ordinary skill in the art that the optimal dosage of the active ingredient(s) in the pharmaceutical composition will depend on a variety of factors. Relevant factors include, without limitation, the type of subject (e.g., human), the overall health of the subject, the type of condition the subject has, the use of the composition as part of a multi-drug regimen, the particular form of the composition, and the manner of administration.
  • the pharmaceutical compositions comprise an effective amount of a composition such that a suitable dosage will be obtained.
  • carrier refers to a diluent, adjuvant or excipient, with which a composition comprising a conjugate is administered. Any auxiliary, stabilizing, thickening, lubricating and Attorney Docket No.074530/614073 coloring agents can be used.
  • the compositions and pharmaceutically acceptable carriers when administered to a subject, are sterile. Water may be a carrier when the composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • the present compositions if desired, can also contain minor amounts of pH buffering agents.
  • the liquid pharmaceutical compositions can also include one or more of the following: sterile diluents such as water for injection, saline solution, physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which can serve as the solvent or suspending medium, polyethylene glycols, glycerin, cyclodextrin, propylene glycol, or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates; agents for the adjustment of pH such as hydrochloric acid; and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • sterile diluents such as water for injection, saline solution, physiological saline, Ringer’s solution, isotonic sodium chloride
  • a parenteral composition can be enclosed in an ampoule, a disposable syringe, or a multiple-dose vial made of glass, plastic or other material.
  • physiological saline is an adjuvant.
  • An injectable composition may be sterile.
  • the present compositions can take the form of solutions, suspensions, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. Examples of suitable pharmaceutical carriers are described in Remington’s Pharmaceutical Sciences by E.W. Martin.
  • the compositions are formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human subjects.
  • the carriers or vehicles for intravenous administration are sterile isotonic aqueous buffer solutions.
  • the compositions can also include a solubilizing agent.
  • Compositions for intravenous administration can optionally comprise a local anesthetic such as lignocaine to ease pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent.
  • compositions are to be administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or Attorney Docket No.074530/614073 saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
  • the pharmaceutical compositions can be prepared using methodology well known in the pharmaceutical art.
  • a composition intended to be administered by injection can be prepared by combining a composition with water so as to form a solution.
  • a surfactant can be added to facilitate the formation of a homogeneous solution or suspension.
  • Surfactants are complexes that can non-covalently interact with a composition so as to facilitate dissolution or homogeneous suspension of the composition in the aqueous delivery system.
  • the conjugates described herein can be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal, and intestinal mucosa, etc.). Administration can be systemic or local.
  • Various delivery systems are known, e.g., microparticles, microcapsules, capsules, etc., and may be useful for administering a composition that comprises the conjugate.
  • Methods of administration may include, but are not limited to, oral administration and parenteral administration; parenteral administration including, but not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous; intranasal, epidural, sublingual, intranasal, intracerebral, intraventricular, intrathecal, intravaginal, transdermal, rectally, by inhalation, or topically to the ears, nose, eyes, or skin.
  • the mode of administration is left to the discretion of the practitioner, and will depend, in-part, upon the site of the medical condition.
  • the conjugate is administered intravenously, subcutaneously, or intramuscularly. [095]
  • the conjugates are administered parenterally.
  • the conjugates are administered intravenously. In certain embodiments, the conjugates are administered by continuous infusion. In certain embodiments, the conjugates are administered by an infusion that lasts for 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, or 2 hours. [096] In certain embodiments, it can be desirable to administer conjugates locally to the area in need of treatment.
  • conjugates can be injected intraperitoneally.
  • the conjugates can be delivered in a controlled release system.
  • PE CD221 (IGF-1R) antibody (clone 1H7, BD Biosciences) and an eFluor780 live/dead dye (eBiosciences) were added to each sample and incubated for 30 minutes at 4 °C in the dark.
  • a PE Mouse IgG1, ⁇ isotype control (BD Bioscience) was used to set the isotype control for each cell line. Then, 2 mL of PBS was added to each sample, the cells were gently resuspended and centrifuged at 500 ⁇ g for 5 minutes and the supernatant was discarded.
  • the cells were subcultured using TrypLE at a subcultivation ratio of 1:3 to 1:6 when the cell culture reached approximately 80% confluence. Table 6.
  • the cells were collected during logarithmic growth using TrypLE and counted.
  • the number of cells indicated in Table 7 was seeded in 100 ⁇ L per well of a 96-well plate according to the plate layout shown below. The plates were incubated overnight at 37°C, 5% CO 2 . Table 7.
  • Test Conjugate Concentration* Formulation Final concentration r ange (nEq/mL) [0105] A 1/10 working stock solution of LX-101 was prepared in 1 mM HC1, such that the concentration of the working stock solution was 0.4 ⁇ Eq/ml of drug in 1.9 mM HCl. Sterile Eppendorf tubes were prepared containing 3x the final well concentrations in the medium corresponding to each cell line (Table 6). The first dilution was prepared using the 1/10 working stock diluted in media. Subsequent 2.5-fold dilutions were prepared using media. A visual check was performed for signs of precipitation when the compound was diluted in media.
  • a 10 mM HCl stock solution was prepared by diluting HCl in cell culture grade water and the pH was confirmed to be between 1 and 3.
  • a working stock solution was prepared with a final concentration of 1.9 mM HCl.
  • 75 ⁇ L of the working stock solution was added to 425 ⁇ l media to make 3x final concentration of 285 ⁇ M HCl.
  • 50 ⁇ L of the prepared dilutions of LX-101 or HCl was added to the appropriate wells, providing a total volume of 150 ⁇ L per well. Unused wells were filled with 150 ⁇ L of PBS.
  • LX-101 exhibits absolute IC 50 s less than 70 nM (based on the concentration of IGF-1R ligand which includes approximately 8 covalently bound methotrexate molecules) in certain cell lines of pharyngeal cancer, triple negative breast cancer, bladder cancer, lung cancer, colorectal cancer, prostate cancer, pancreas cancer, liver cancer, and esophagus Attorney Docket No.074530/614073 cancer, ovarian cancer, kidney cancer and stomach cancer cell lines, indicating substantial anti- cancer properties.
  • LX-101 was highly cytotoxic to pharyngeal line FaDU, bladder line 5637, prostate line DU 145, liver line Hep G2, esophagus line KYSE-70, and kidney line 786- O, with remarkably low absolute IC50 values of less than 10 nM. Table 10.

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Abstract

La présente invention concerne des méthodes de traitement d'un cancer lié au récepteur du facteur de croissance insulinique 1 (IGF-1R) chez un sujet, la méthode comprenant l'administration au sujet d'un conjugué comprenant un ligand d'IGF-1R, ou une partie ou un variant de celui-ci, et un agent cytotoxique.
PCT/US2024/031615 2023-05-31 2024-05-30 Méthodes de traitement de cancers liés à l'igf-1r avec un ligand du récepteur du facteur de croissance insulinique 1 conjugué à un agent cytotoxique Ceased WO2024249596A2 (fr)

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EP24816394.1A EP4719451A2 (fr) 2023-05-31 2024-05-30 Méthodes de traitement de cancers liés à l'igf-1r avec un ligand du récepteur du facteur de croissance insulinique 1 conjugué à un agent cytotoxique
AU2024279572A AU2024279572A1 (en) 2023-05-31 2024-05-30 Methods for treating igf-1r-related cancers with an insulin-like growth factor 1 receptor ligand conjugated to a cytotoxic agent
CN202480047411.8A CN121586579A (zh) 2023-05-31 2024-05-30 用于用与细胞毒性剂缀合的胰岛素样生长因子1受体配体治疗igf-1r相关癌症的方法
KR1020257043392A KR20260020410A (ko) 2023-05-31 2024-05-30 세포독성 제제에 접합된 인슐린 유사 성장 인자 1 수용체 리간드를 이용한 igf-1r 관련 암의 치료 방법

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