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Publication Number
US-8747847-B2
Publication Date
2014-06-10
Expiration Date
Abstract
The present invention relates to methods for inhibiting tumor growth, increasing survival of a subject having a tumor and inducing protection against tumor recurrence in a mammal. The methods comprise administering a humanized monoclonal antibody comprising CDR regions derived from the murine monoclonal antibody designated mBAT-1, in combination with at least one chemotherapeutic agent.
Core Innovation
The invention relates to treating a tumor and preventing tumor recurrence by administering a humanized monoclonal antibody BAT (mBAT-1) and/or a fragment thereof. The humanized antibody includes all complementarity determining regions (CDRs) of mBAT-1 and a framework region (FR) from an acceptor human immunoglobulin, or modified therefrom.
A key feature is the humanization of the mBAT-1 antibody by grafting mBAT-1 CDRs onto human framework regions, including specified variable-region sequence/SEQ ID combinations for heavy- and light-chain variable regions. The humanized antibody is administered alone or in combination with chemotherapy, and the document further addresses treatment timing in which the humanized antibody is administered between 1 and 30 days prior to commencing chemotherapy.
The document reports unexpected synergistic antitumor effects when the humanized antibody is combined with chemotherapy, compared with monotherapies. It describes enhanced survival of lymphocytes and effector-memory CD4+CD45RO+ T cells, improved tolerability at chemotherapy dose-limiting toxicity levels, durable complete remissions in mouse tumor models, and tumor-specific immunological memory after cure and rechallenge.
Claims Coverage
The provided content includes two independent claims that cover treating a tumor or enhancing survival and improving tolerability to chemotherapy. Across these independent claims, the inventive features include a humanized BAT (mBAT-1) antibody architecture, specified chemotherapy agent selection, and a defined administration timing relationship of the humanized antibody relative to chemotherapy.
Humanized BAT antibody architecture with mBAT-1 CDRs and acceptor human FR
The antibody or fragment has all complementarity determining regions of mBAT-1 and a framework region (FR) from an acceptor human immunoglobulin, or modified therefrom.
Combination treatment with selected chemotherapeutic agents
Administering an effective amount of at least one chemotherapeutic agent selected from 5-fluorouracil, cytarabine, oxaliplatin, paclitaxel and combinations thereof in addition to the humanized BAT (mBAT-1) antibody or fragment.
Antibody administered between 1 and 30 days prior to commencing chemotherapy
Administering the humanized antibody between 1 and 30 days prior to commencing chemotherapy.
Improving tolerability during chemotherapy by administering humanized BAT
Improving tolerability to at least one chemotherapeutic agent by administering an effective amount of the humanized BAT (mBAT-1) antibody or fragment to a subject undergoing chemotherapy with the selected chemotherapeutic agent(s).
Overall, the claim coverage centers on using a humanized BAT (mBAT-1) antibody defined by mBAT-1 CDRs grafted onto an acceptor human immunoglobulin framework region, combined with specified chemotherapeutic agents, with the humanized antibody administered before chemotherapy to support tumor treatment, survival enhancement, or improved chemotherapy tolerability.
Stated Advantages
Unexpected synergistic antitumor effects versus monotherapies.
Improved survival of lymphocytes and effector-memory CD4+CD45RO+ T cells.
Enhanced tolerability at chemotherapy dose-limiting toxicity levels.
Durable complete remissions in mouse tumor models.
Tumor-specific immunological memory after cure and rechallenge.
Documented Applications
Treating tumors and preventing recurrence, including use in combination with chemotherapy.
Use in Phase I clinical trial context for advanced hematologic malignancies, including AML, CLL, NHL, HL, and multiple myeloma.
Tumor model applications reporting durable complete remissions and immune memory.
Improving tolerability to chemotherapy in subjects undergoing chemotherapy with selected agents.
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