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Publication Number
US-9309308-B2
Publication Date
2016-04-12
Expiration Date
Abstract
A method of treating a tumor or enhancing survival of a subject having a tumor. The method includes (i) administering to a subject in need thereof an effective amount of a humanized monoclonal antibody or a fragment thereof, wherein the antibody or the fragment thereof has all complementarity determining regions of murine monoclonal antibody BAT (mBAT-1) and a framework region (FR) from an acceptor human immunoglobulin, or modified therefrom; and (ii) administering to the subject an effective amount of at least one chemotherapeutic agent selected from the group consisting of: 5-fluorouracil, cytarabine, oxaliplatin, paclitaxel and combinations thereof. The humanized antibody is administered between 1 and 30 days after commencing chemotherapy or substantially simultaneously or concurrently or according to an overlapping schedule with the at least one chemotherapeutic agent to thereby treat the tumor or enhance the survival of the subject having the tumor.
Core Innovation
The invention provides a humanized monoclonal antibody BAT (mBAT-1) comprising complementarity determining regions (CDRs) of murine monoclonal antibody BAT (mBAT-1) and a framework region from an acceptor human immunoglobulin, or modified therefrom. The humanized BAT (mBAT-1)-based monoclonal antibody is described in connection with a specific antibody example, CT-011/hBAT-1, and is used with chemotherapy to treat a tumor and/or enhance survival of a subject having the tumor.
The invention addresses treatment timing and regimen relationships between the humanized antibody and chemotherapy, describing administration between 1 and 30 days after commencing chemotherapy and alternating schedule concepts between the antibody and at least one chemotherapeutic agent. Regimens can be substantially simultaneous, concurrent, overlapping, alternating, sequential/successive, and sequential versus concomitant, to support therapeutic effects with chemotherapeutic agent classes including 5-fluorouracil, cytarabine, oxaliplatin, paclitaxel, cisplatin, irinotecan (SN-38), cyclophosphamide, doxorubicin, dacarbazine, docetaxel, etoposide, vinblastine/vincristine/vinorelbine, and bevacizumab and VEGF variants.
The invention is directed to objectives including tumor growth inhibition, survival enhancement, increased tolerability to DLT-level chemotherapy, and reduction or prevention of tumor recurrence via immunological memory. Documented evidence includes in vitro synergy of lymphocyte viability with chemotherapy, in vivo efficacy in mouse tumor models with 5-FU, paclitaxel, cisplatin, irinotecan, and oxaliplatin, and tumor recurrence protection upon re-challenge showing memory effects with tumor-type specificity.
The document further reports clinical evidence from a phase I trial in which CT-011 is safe and well tolerated, and a subset of patients with advanced hematologic malignancy exhibits extended survival and at least one complete response with durable remission after single-dose CT-011. The overall described approach therefore combines a humanized BAT (mBAT-1)-based monoclonal antibody with chemotherapy using defined timing/regimen relationships to achieve anti-tumor and survival outcomes while also targeting recurrence through immunological memory.
Claims Coverage
The independent claims identify at least two inventive feature themes involving a humanized BAT (mBAT-1) antibody with an acceptor human immunoglobulin framework and specified chemotherapeutic agents under defined administration timing or alternating schedules.
Humanized BAT mBAT-1 antibody with acceptor-human FR combined with defined chemo agents
Administering an effective amount of a humanized monoclonal antibody (or fragment) having all complementarity determining regions of murine monoclonal antibody BAT (mBAT-1) and a framework region from an acceptor human immunoglobulin (or a modified version), together with administering an effective amount of at least one chemotherapeutic agent selected from 5-fluorouracil, cytarabine, oxaliplatin, paclitaxel, cisplatin, and combinations thereof.
Administer antibody 1 to 30 days after commencing chemotherapy or alternating schedule
Administering the humanized antibody between 1 and 30 days after commencing chemotherapy or according to an alternating schedule with the at least one chemotherapeutic agent, thereby treating the tumor or enhancing survival.
Improving tolerability to chemotherapy using humanized mBAT-1 antibody within 1 to 30 days or alternating schedule
Improving tolerability to at least one chemotherapeutic agent by administering to a subject in need thereof an effective amount of a humanized monoclonal antibody BAT (mBAT-1) (or fragment) having all complementarity determining regions of mBAT-1 and a framework region from an acceptor human immunoglobulin (or modified therefrom), while the subject is undergoing chemotherapy with at least one chemotherapeutic agent selected from 5-fluorouracil, cytarabine, oxaliplatin, paclitaxel, cisplatin, and combinations thereof, with the humanized antibody administered between 1 and 30 days after commencing chemotherapy or according to an alternating schedule.
Claim coverage centers on humanized BAT (mBAT-1) antibody molecules defined by mBAT-1 CDRs plus an acceptor-human Ig framework, administered with specified chemotherapeutic agents. The independent claims further require a timing relationship or an alternating schedule to support treating tumors, enhancing survival, and improving tolerability to the chemotherapeutic agents.
Stated Advantages
Treating a tumor.
Enhancing survival of a subject having the tumor.
Improving tolerability to at least one chemotherapeutic agent.
Reducing or preventing tumor recurrence.
Documented Applications
Treatment of a tumor and/or enhancing survival of a subject having the tumor using CT-011/hBAT-1 (humanized BAT (mBAT-1)-based monoclonal antibody) with chemotherapy regimens.
Improving tolerability to DLT-level chemotherapy as described in connection with chemotherapy combinations with the humanized BAT (mBAT-1)-based monoclonal antibody.
Tumor recurrence protection upon re-challenge, including immunological memory with tumor-type specificity.
Clinical application in a phase I trial context for patients with advanced hematologic malignancy, reporting safety/well tolerated results and survival/complete response outcomes for a subset of patients.
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