Methods for treatment of patients with myelodysplastic syndromes
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Publication Number
US-12083192-B2
Publication Date
2024-09-10
Expiration Date
Abstract
Methods for treating a proliferative disease in hematologic malignancy in a subject having a complex karyotype by administering an effective amount of an immunotherapy which includes a targeting agent for an epitope of CD33. The proliferative disease may be a hematological disease or disorder such as multiple myeloma, acute myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasm. The effective amount of the anti-CD33 targeting agent may be an amount sufficient to induce myeloconditioning or an amount to induce myeloablation. The methods may further include transplanting allogeneic stem cells to the patient after administration of the anti-CD33 targeting agent.
Core Innovation
The disclosed invention relates to treating a hematologic malignancy in a subject by administering an anti-CD33 targeting agent to induce myeloconditioning or myeloablation. The treatment is directed to subjects having complex karyotype and/or a p53 mutation, with the hematologic malignancy comprising myelodysplastic syndrome (MDS), multiple myeloma (MM), acute myeloid leukemia (AML), myeloproliferative neoplasm, or a combination thereof. The anti-CD33 targeting agent comprises lintuzumab, gemtuzumab, or vadastuximab and is radiolabeled with selected isotopes including 131I or 225Ac.
A further aspect is a determination-based approach for MDS, wherein a subject is evaluated to determine if the subject has a complex karyotype as indicated by the MDS categorized as a poor or very poor cytogenetic prognostic subgroup in IPSS-R. If the subject has the complex karyotype, the method proceeds with administration of an effective amount of the anti-CD33 targeting agent. In this context, the anti-CD33 targeting agent is 131I- or 225Ac-labeled and is administered as a single bolus or infusion in a subject-specific dose.
Another aspect evaluates whether a subject has one or both of a mutated p53 gene or a mutant form of p53 protein, and if so proceeds with administration of an effective amount of a radiolabeled anti-CD33 targeting agent comprising lintuzumab. The described regimens specify that the anti-CD33 targeting agent is administered as a single bolus or infusion with a subject-specific dose including radiation dose and total protein dose constraints. In contemplated workflows, myeloablation can be followed by allogeneic stem cell transplantation at a post-administration window.
Claims Coverage
The independent claims are clm-00001, clm-00013, and clm-00016. Across these independent claims, the coverage centers on administering a radiolabeled anti-CD33 targeting agent to subjects with complex karyotype and/or mutated p53 status, to induce myeloconditioning or myeloablation, with specific attention to MDS and subject-specific single bolus or infusion dosing, and optionally proceeding to allogeneic stem cell transplantation after myeloablation.
Anti-CD33 targeting agent induces myeloconditioning or myeloablation in complex karyotype or p53 mutation
A method of treating a hematologic malignancy by administering an effective amount of an anti-CD33 targeting agent to a subject having a complex karyotype or a p53 mutation, wherein the hematologic malignancy comprises MDS, MM, AML, myeloproliferative neoplasm, or a combination thereof, and wherein the effective amount is sufficient to induce myeloconditioning or myeloablation.
Radiolabeled lintuzumab or other anti-CD33 agent selected isotopes
The anti-CD33 targeting agent comprises a radiolabel selected from the group consisting of 131I, 125I, 123I, 90Y, 177Lu, 186Re, 188Re, 89Sr, 153Sm, 32P, 225Ac, 213Bi, 213Po, 211At, 212Bi, 213Bi, 223Ra, 227Th, 149Tb, 137Cs, 212Pb, and 103Pd, and comprises lintuzumab, gemtuzumab, or vadastuximab.
IPSS-R poor or very poor cytogenetic subgroup complex karyotype with 131I- or 225Ac-labelled lintuzumab dosing
A method for treating a subject having MDS by determining if the subject has a complex karyotype as indicated by the MDS categorized as a poor or very poor cytogenetic prognostic subgroup in IPSS-R, and if so proceeding with administration of an effective amount of a 131I- or 225Ac-labelled anti-CD33 targeting agent administered as a single bolus or infusion in a subject specific dose comprising a radiation dose of 0.1 to 10 uCi/kg body weight and a total protein dose of less than 16 mg/kg body weight, wherein the anti-CD33 targeting agent comprises lintuzumab.
Mutated p53 gene or mutant p53 protein with 131I- or 225Ac-labelled lintuzumab dosing
A method for treating a subject having MDS by determining if the subject has one or both of a mutated p53 gene or a mutant form of p53 protein, and if so proceeding with administration of an effective amount of a 131I- or 225Ac-labelled anti-CD33 targeting agent administered as a single bolus or infusion in a subject specific dose comprising a radiation dose of 0.1 to 10 uCi/kg body weight and a total protein dose of less than 16 mg/kg body weight, wherein the anti-CD33 targeting agent comprises lintuzumab.
Across the independent claims, coverage is directed to using a radiolabeled anti-CD33 targeting agent comprising lintuzumab, gemtuzumab, or vadastuximab to treat hematologic malignancies—including MDS—in subjects defined by complex karyotype and/or p53 mutation status. The independent claims further specify MDS workflow based on IPSS-R poor or very poor cytogenetic subgroup complex karyotype or mutated p53 determination, and they require single bolus or infusion subject-specific dosing of 131I- or 225Ac-labelled lintuzumab with defined radiation dose and total protein dose limits, with an inducement of myeloconditioning or myeloablation as the treatment purpose.
Stated Advantages
Documented Applications
Treating a hematologic malignancy in a subject by administering a radiolabeled anti-CD33 targeting agent to induce myeloconditioning or myeloablation in subjects with complex karyotype or p53 mutation, where the hematologic malignancy comprises MDS, MM, AML, myeloproliferative neoplasm, or a combination thereof.
Treating MDS by determining if the subject has a complex karyotype as indicated by the MDS categorized as a poor or very poor cytogenetic prognostic subgroup in IPSS-R, and if so administering an effective amount of 131I- or 225Ac-labelled anti-CD33 targeting agent comprising lintuzumab.
Treating MDS by determining if the subject has one or both of a mutated p53 gene or a mutant form of p53 protein, and if so administering an effective amount of 131I- or 225Ac-labelled anti-CD33 targeting agent comprising lintuzumab.
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