Journal Articles

Antibody-based therapy

Therapies based on monoclonal antibodies, antibody derivatives, antibody-drug conjugates, bispecific antibodies, immunotoxins, etc. (except for immune checkpoint therapies)

A GPC3-targeting Bispecific Antibody, GPC3-S-Fab, with Potent Cytotoxicity

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This protocol describes the construction and functional studies of a bispecific antibody (bsAb), GPC3-S-Fab. bsAbs can recognize two different epitopes through their two different arms. bsAbs have been actively studied for their ability to directly recruit immune cells to kill tumor cells. Currently, the majority of bsAbs are produced in the form of recombinant proteins, either as Fc-containing bsAbs or as smaller bsAb derivatives without the Fc region. In this study, GPC3-S-Fab, an antibody fragment (Fab) based bispecific antibody, was designed by linking the Fab of anti-GPC3 antibody GC33 with an anti-CD16 single domain antibody. The GPC3-S-Fab can be expressed in Escherichia coli and purified by two affinity chromatographies. The purified GPC3-S-Fab can specifically bind to and kill GPC3 positive liver cancer cells by recruiting natural killer cells, suggesting a potential application of GPC3-S-Fab in liver cancer therapy.

Author Info: (1) School of Pharmaceutical Sciences, Sun Yat-Sen University; Center for Cellular & Structural Biology, Sun Yat-Sen University. (2) School of Pharmaceutical Sciences, Sun Yat-Sen University

Author Info: (1) School of Pharmaceutical Sciences, Sun Yat-Sen University; Center for Cellular & Structural Biology, Sun Yat-Sen University. (2) School of Pharmaceutical Sciences, Sun Yat-Sen University; Center for Cellular & Structural Biology, Sun Yat-Sen University. (3) School of Pharmaceutical Sciences, Sun Yat-Sen University; Center for Cellular & Structural Biology, Sun Yat-Sen University. (4) School of Pharmaceutical Sciences, Sun Yat-Sen University; Center for Cellular & Structural Biology, Sun Yat-Sen University. (5) School of Pharmaceutical Sciences, Sun Yat-Sen University; Center for Cellular & Structural Biology, Sun Yat-Sen University. (6) School of Pharmaceutical Sciences, Sun Yat-Sen University; Center for Cellular & Structural Biology, Sun Yat-Sen University; liqing66@mail.sysu.edu.cn. (7) School of Pharmaceutical Sciences, Sun Yat-Sen University; Center for Cellular & Structural Biology, Sun Yat-Sen University; wangzh357@mail.sysu.edu.cn.

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Boosting half-life and effector functions of therapeutic antibodies by Fc-engineering: An interaction-function review

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Due mainly to their high level of affinity and specificity, therapeutic monoclonal antibodies (mAbs) have been frequently selected as treatment for cancer, autoimmune or chronic inflammatory diseases. Despite the increasing number of mAbs and related products in the biopharmaceutical market, they are still expensive, can cause undesired side effects, and eventually cause resistance. Antibody engineering, which emerged to overcome limitations faced by mAb therapy, has supported the development of modified mAbs for immunotherapy. As part of this approach, researchers have invested in obtaining antibody fragments, as well as in Fc region modifications, since interactions with Fc receptors influence an antibody's half-life and mechanism of action. Thus, Fc engineering results in antibodies with more desirable characteristics and functions for which they are intended, creating "fit-for-purpose" antibodies with reduced side effects. Furthermore, aglycosylated antibodies, produced in bacterial cultivation, have been an alternative to create new effector functional human immunotherapeutics, while reducing mAb therapy costs. This review highlights some features that enhance mAb performance, related to the improvement of antibody half-life and effector responses by both Fc-engineering and glycoengineering.

Author Info: (1) Fundacao Oswaldo Cruz, Fiocruz Ceara, Eusebio, CE 61760-000, Brazil. Electronic address: marcela.gambim@fiocruz.br. (2) Fundacao Oswaldo Cruz, Fiocruz Ceara, Eusebio, CE 61760-000, Brazil. (3) Fundacao

Author Info: (1) Fundacao Oswaldo Cruz, Fiocruz Ceara, Eusebio, CE 61760-000, Brazil. Electronic address: marcela.gambim@fiocruz.br. (2) Fundacao Oswaldo Cruz, Fiocruz Ceara, Eusebio, CE 61760-000, Brazil. (3) Fundacao Oswaldo Cruz, Fiocruz Ceara, Eusebio, CE 61760-000, Brazil. (4) Fundacao Oswaldo Cruz, Fiocruz Ceara, Eusebio, CE 61760-000, Brazil. (5) Fundacao Oswaldo Cruz, Fiocruz Ceara, Eusebio, CE 61760-000, Brazil.

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Production of a mouse monoclonal IgM antibody that targets the carbohydrate Thomsen-nouveau cancer antigen resulting in in vivo and in vitro tumor killing

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The construction of a tumor-associated carbohydrate antigen-zwitterionic polysaccharide conjugate, Thomsen-nouveau-polysaccharide A1 (Tn-PS A1, where Tn = D-GalpNAc), has led to the development of a carbohydrate binding monoclonal antibody named Kt-IgM-8. Kt-IgM-8 was produced via hybridoma from Tn-PS A1 hyperimmunized Jackson Laboratory C57BL/6 mice, splenocytes and the murine myeloma cell line Sp2/0Ag14 with subsequent cloning on methyl cellulose semi-solid media. This in-house generated monoclonal antibody negates binding influenced from peptides, proteins, and lipids and preferentially binds monovalent Tn antigen as noted by ELISA, FACS, and glycan array technologies. Kt-IgM-8 demonstrated in vitro and in vivo tumor killing against the Michigan Cancer Foundation breast cell line 7 (MCF-7). In vitro tumor killing was observed using an LDH assay that measured antibody-induced complement-dependent cytotoxicity and these results were validated in an in vivo passive immunotherapy approach using an MCF-7 cell line-derived xenograft model. Kt-IgM-8 is effective in killing tumor cells at 30% cytotoxicity, and furthermore, it demonstrated approximately 40% reduction in tumor growth in the MCF-7 model.

Author Info: (1) Department of Chemistry and Biochemistry, School of Green Chemistry and Engineering, The University of Toledo, 2801 West Bancroft Street, Wolfe Hall 2232B, Toledo, OH

Author Info: (1) Department of Chemistry and Biochemistry, School of Green Chemistry and Engineering, The University of Toledo, 2801 West Bancroft Street, Wolfe Hall 2232B, Toledo, OH, 43606, USA. (2) Department of Chemistry and Biochemistry, School of Green Chemistry and Engineering, The University of Toledo, 2801 West Bancroft Street, Wolfe Hall 2232B, Toledo, OH, 43606, USA. (3) Department of Chemistry and Biochemistry, School of Green Chemistry and Engineering, The University of Toledo, 2801 West Bancroft Street, Wolfe Hall 2232B, Toledo, OH, 43606, USA. (4) Department of Chemistry and Biochemistry, School of Green Chemistry and Engineering, The University of Toledo, 2801 West Bancroft Street, Wolfe Hall 2232B, Toledo, OH, 43606, USA. (5) Siamab Therapeutics, Inc., Newton, MA, 02458, USA. (6) Siamab Therapeutics, Inc., Newton, MA, 02458, USA. (7) Department of Chemistry and Biochemistry, School of Green Chemistry and Engineering, The University of Toledo, 2801 West Bancroft Street, Wolfe Hall 2232B, Toledo, OH, 43606, USA. peter.andreana@utoledo.edu.

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Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia

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This is a pivotal, multicenter, open-label study of moxetumomab pasudotox, a recombinant CD22-targeting immunotoxin, in hairy cell leukemia (HCL), a rare B cell malignancy with high CD22 expression. The study enrolled patients with relapsed/refractory HCL who had >/=2 prior systemic therapies, including >/=1 purine nucleoside analog. Patients received moxetumomab pasudotox 40 microg/kg intravenously on days 1, 3, and 5 every 28 days for

Author Info: (1) National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (2) The Royal Marsden NHS Foundation Trust, London, UK. (3) Institute of Hematology, Seragnoli

Author Info: (1) National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (2) The Royal Marsden NHS Foundation Trust, London, UK. (3) Institute of Hematology, Seragnoli University of Bologna, Bologna, Italy. (4) Hospital Clinic, Barcelona, Spain. (5) Centre Hospitalier Lyon Sud, Pierre-benite, France. (6) Medical University of Lodz, Copernicus Memorial Hospital, Lodz, Poland. (7) Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA. (8) Charite Universitatsmedizin, Berlin, Germany. (9) Universitatsklinikum Heidelberg, Heidelberg, Baden-Wurttemberg, Germany. (10) Clinical Center of Serbia, Belgrade, Serbia. (11) University of Alberta, Edmonton, Alberta, Canada. (12) Ghent University Hospital, Ghent, Belgium. (13) David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. (14) Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA. (15) St. James's Hospital, Dublin, Ireland. (16) Azienda Ospedaliera Universitaria, University of Siena, Siena, Italy. (17) Service d'hematologie, CHU Bordeaux, F-33000, Bordeaux, France. (18) Ziekenhuis Netwerk Antwerpe, Antwerp, Belgium. (19) Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy. (20) Northwestern Medicine Feinberg School of Medicine, Chicago, IL, USA. (21) Masaryk University, Brno, Czech Republic. (22) Helse Bergen HF Haukeland University Hospital, Bergen, Norway. (23) Clinic of Hematology, Ospedale Policlinico San Martino, Genova, Italy. (24) Department of Hematology and Transplantation, Medical University of Gdansk, Gdansk, Poland. (25) Inserm U1245 and Department of Hematology, Centre Henri Becquerel and Normandie Univ UNIROUEN, Rouen, France. (26) SOL, Clinique Sainte-Anne, Strasbourg, France. (27) MD Anderson Cancer Center, Houston, TX, USA. (28) Centre Hospitalier de Versailles, INSERM U1173, Le Chesnay, France. Universite Versailles Saint-Quentin-en-Yvelines, Paris Saclay, France. (29) Justus-Liebig University, Giessen, Germany. (30) City of Hope National Medical Center, Duarte, CA, USA. (31) Bnai Zion Medical Center, Haifa, Israel. (32) L'hopital Cote de Nacre, Caen Cedex 9, Caen, France. (33) University of New Mexico, Albuquerque, NM, USA. (34) University of Turin, Turin, Italy. (35) Weill Cornell Medicine, The New York Presbyterian Hospital, New York, NY, USA. (36) MedImmune, South San Francisco, CA, USA. (37) MedImmune, South San Francisco, CA, USA. (38) MedImmune, Gaithersburg, MD, USA. (39) MedImmune, Gaithersburg, MD, USA. (40) National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (41) National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (42) MedImmune, Gaithersburg, MD, USA. (43) Developmental Therapeutics Consortium, Chicago, IL, USA. frankgiles@aol.com.

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A novel, fully human anti-fucosyl-GM1 antibody demonstrates potent in vitro and in vivo antitumor activity in preclinical models of small cell lung cancer

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PURPOSE: The ganglioside fucosyl-GM1 (FucGM1) is a tumor-associated antigen expressed in a large percentage of human small cell lung cancer (SCLC) tumors, but absent in most normal adult tissues, making it a promising target in immuno-oncology. This study was undertaken to evaluate the preclinical efficacy of BMS-986012, a novel, nonfucosylated, fully human IgG1 antibody that binds specifically to FucGM1. EXPERIMENTAL DESIGN: The antitumor activity of BMS-986012 was evaluated in in vitro assays using SCLC cells and in mouse xenograft and syngeneic tumor models, with and without chemotherapeutic agents and checkpoint inhibitors. RESULTS: BMS-986012 showed high binding affinity for FcgammaRIIIa, which resulted in enhanced antibody-dependent cellular cytotoxicity against FucGM1-expressing tumor cells. BMS-986012-mediated tumor cell killing was also observed in complement-dependent cytotoxicity and antibody-dependent cellular phagocytosis assays. In mouse SCLC models, BMS-986012 demonstrated efficacy and was well tolerated. In the DMS79 xenograft model, tumor regression was achieved with BMS-986012 doses of 0.3 mg/kg and greater; antitumor activity was enhanced when BMS-986012 was combined with standard-of-care cisplatin or etoposide. In a syngeneic model, tumors derived from a genetically engineered model of SCLC were treated with BMS-986012 or anti-FucGM1 with a mouse IgG2a Fc and their responses evaluated; when BMS-986012 was combined with anti-PD-1 or anti-CD137 antibody, responses significantly improved. CONCLUSIONS: Single agent BMS-986012 demonstrated robust antitumor activity, with the addition of chemotherapeutic or immunomodulatory agents further inhibiting SCLC growth in the same models. These preclinical data supported evaluation of BMS-986012 in a phase 1 clinical trial of patients with relapsed, refractory SCLC.

Author Info: (1) Bristol-Myers Squibb (United States). (2) Pharmacology, Biologics Discovery, Bristol-Myers Squibb (United States). (3) Cell Biology & Physiology, Bristol-Myers Squibb (United States). (4) Bristol-Myers Squibb

Author Info: (1) Bristol-Myers Squibb (United States). (2) Pharmacology, Biologics Discovery, Bristol-Myers Squibb (United States). (3) Cell Biology & Physiology, Bristol-Myers Squibb (United States). (4) Bristol-Myers Squibb (United States). (5) Bristol-Myers Squibb (United States). (6) Bristol-Myers Squibb (United States). (7) Biologics Discovery California, Bristol-Myers Squibb (United States). (8) Bristol-Myers Squibb (United States). (9) Biologics Discovery California, Bristol-Myers Squibb (United States). (10) Cancer Biology, Medarex inc. (11) Bristol-Myers Squibb (United States). (12) Pediatrics and Genetics, Stanford University. (13) Microbiology, Immunology, and Cancer Biology, University of Virginia. (14) Departments of Pediatrics and Genetics, Stanford University School of Medicine. (15) Cell Biology & Physiology, Bristol-Myers Squibb pina_cardarelli@comcast.net.

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High-Throughput, Multispecies, Parallelized Plasma Stability Assay for the Determination and Characterization of Antibody-Drug Conjugate Aggregation and Drug Release

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The stability of antibody-drug conjugates (ADCs) in circulation is critical for maximum efficacy and minimal toxicity. An ADC reaching the intended target intact can deliver the highest possible drug load to the tumor and reduce off-target toxicity from free drug in the blood. As such, assessment of ADC stability is a vital piece of data during development. However, traditional ADC stability assays can be manually intensive, low-throughput, and require large quantities of ADC material. Here, we introduce an automated, high-throughput plasma stability assay for screening drug release and aggregation over 144 h for up to 40 ADCs across five matrices simultaneously. The amount of ADC material during early drug development is often limited, so this assay was implemented in 384-well format to minimize material requirements to <100 mug of each ADC and 100 muL of plasma per species type. Drug release and aggregation output were modeled using nonlinear regression equations to calculate formation rates for each data type. A set of 15 ADCs with different antibodies and identical valine-citrulline-p-aminobenzylcarbamate-monomethylauristatin E linker-drug payloads was tested and formation rates were compared across ADCs and between species, revealing several noteworthy trends. In particular, a wide range in aggregation was found when altering only the antibody, suggesting a key role for plasma stability screening early in the development process to find and remove antibody candidates with the potential to create unstable ADCs. The assay presented here can be leveraged to provide stability data on new chemistry and antibody screening initiatives, select the best candidate for in vivo studies, and provide results that highlight stability issues inherent to particular ADC designs throughout all stages of ADC development.

Author Info: (1) Drug Metabolism and Pharmacokinetics and Drug Product Development, AbbVie, Inc., 1 N. Waukegan Drive, North Chicago, Illinois 60064, United States. (2) Drug Metabolism and

Author Info: (1) Drug Metabolism and Pharmacokinetics and Drug Product Development, AbbVie, Inc., 1 N. Waukegan Drive, North Chicago, Illinois 60064, United States. (2) Drug Metabolism and Pharmacokinetics and Drug Product Development, AbbVie, Inc., 1 N. Waukegan Drive, North Chicago, Illinois 60064, United States. (3) Drug Metabolism and Pharmacokinetics and Drug Product Development, AbbVie, Inc., 1 N. Waukegan Drive, North Chicago, Illinois 60064, United States. (4) Drug Metabolism and Pharmacokinetics and Drug Product Development, AbbVie, Inc., 1 N. Waukegan Drive, North Chicago, Illinois 60064, United States. (5) Drug Metabolism and Pharmacokinetics and Drug Product Development, AbbVie, Inc., 1 N. Waukegan Drive, North Chicago, Illinois 60064, United States.

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Population Pharmacokinetics of Gemtuzumab Ozogamicin in Pediatric Patients with Relapsed or Refractory Acute Myeloid Leukemia

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BACKGROUND AND OBJECTIVE: To date, the population pharmacokinetics (popPK) of gemtuzumab ozogamicin (GO), a CD33-directed antibody-drug conjugate consisting of hP67.6 antibody linked to N-acetyl gamma calicheamicin used in the treatment of acute myeloid leukemia (AML), has not been characterized in pediatric patients. This report describes the popPK of GO following intravenous administration in 29 pediatric patients aged

Author Info: (1) Clinical Pharmacology, Oncology, Global Product Development, Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 92121, USA. joanna.c.masters@pfizer.com. (2) Pfizer Global Product Development Oncology

Author Info: (1) Clinical Pharmacology, Oncology, Global Product Development, Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 92121, USA. joanna.c.masters@pfizer.com. (2) Pfizer Global Product Development Oncology, 300 Technology Square, Suite 302, Cambridge, MA, 02139-3520, USA. (3) Clinical Pharmacology, Oncology, Global Product Development, Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 92121, USA.

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FDA Supplemental Approval: Blinatumomab for Treatment of Relapsed and Refractory Precursor B-Cell Acute Lymphoblastic Leukemia

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On July 11, 2017, the Food and Drug Administration granted approval for blinatumomab for the treatment of relapsed or refractory (R/R) precursor B-cell acute lymphoblastic leukemia (ALL). Blinatumomab is a bispecific CD19-directed CD3 T-cell engager. The basis for the approval included results from two clinical trials, TOWER and ALCANTARA. TOWER, a randomized trial comparing overall survival in patients with Philadelphia chromosome (Ph)-negative R/R ALL receiving blinatumomab versus standard-of-care (SOC) chemotherapy, demonstrated a hazard ratio of 0.71 favoring blinatumomab (p = .012; median survival, 7.7 months with blinatumomab and 4.0 months with SOC chemotherapy). Complete remission (CR) rates were 34% for patients receiving blinatumomab and 16% for those receiving SOC. Adverse events were consistent with those observed in prior trials, with cytokine release syndrome and some neurologic events, including tremor, encephalopathy, peripheral neuropathy, and depression, observed more frequently in the blinatumomab arm, whereas neutropenia and infection were less common among patients receiving blinatumomab. Depression emerged as a rare but potentially severe neurologic event associated with blinatumomab. In ALCANTARA, a single-arm trial of blinatumomab in patients with Ph-positive R/R ALL, the CR rate was 31%, and adverse events were similar to those observed previously in Ph-negative R/R ALL. These results support conversion from accelerated to regular approval of blinatumomab for R/R ALL and broadening of the intended population to include both Ph-positive and Ph-negative precursor B-cell R/R ALL. IMPLICATIONS FOR PRACTICE: In TOWER, a randomized trial in patients with relapsed or refractory Philadelphia chromosome (Ph)-negative precursor B-cell acute lymphoblastic leukemia (ALL), treatment with blinatumomab showed superiority over conventional chemotherapy for complete remission (CR) rate (34% vs. 16%) and survival (3.7-month improvement in median; hazard ratio, 0.71). In ALCANTARA, a single-arm trial of blinatumomab for treatment of relapsed or refractory Ph-positive precursor B-cell ALL, the CR rate was 31%. Blinatumomab is now approved for treatment of relapsed or refractory precursor B-cell ALL that is Ph positive or Ph negative.

Author Info: (1) Center for Drug Evaluation and ResearchU.S. Food and Drug Administration, Silver Spring, Maryland, USA elizabeth.pulte@fda.hhs.gov. (2) Center for Drug Evaluation and ResearchU.S. Food and

Author Info: (1) Center for Drug Evaluation and ResearchU.S. Food and Drug Administration, Silver Spring, Maryland, USA elizabeth.pulte@fda.hhs.gov. (2) Center for Drug Evaluation and ResearchU.S. Food and Drug Administration, Silver Spring, Maryland, USA. (3) Center for Drug Evaluation and ResearchU.S. Food and Drug Administration, Silver Spring, Maryland, USA. (4) Center for Drug Evaluation and ResearchU.S. Food and Drug Administration, Silver Spring, Maryland, USA. (5) Center for Drug Evaluation and ResearchU.S. Food and Drug Administration, Silver Spring, Maryland, USA. (6) Center for Drug Evaluation and ResearchU.S. Food and Drug Administration, Silver Spring, Maryland, USA. (7) Center for Drug Evaluation and ResearchU.S. Food and Drug Administration, Silver Spring, Maryland, USA. Oncology Center of Excellence, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. (8) Center for Drug Evaluation and ResearchU.S. Food and Drug Administration, Silver Spring, Maryland, USA. Oncology Center of Excellence, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.

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CARs versus BiTEs: A Comparison between T Cell-Redirection Strategies for Cancer Treatment

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The redirection of T cells against tumors holds much promise for the treatment of cancer. Two main approaches for T-cell redirection involve their genetic modification with chimeric antigen receptors (CAR), or the use of recombinant proteins designated bispecific T-cell engagers (BiTE). These approaches have demonstrated dramatic effects in patients with hematologic cancers, although limited effect against solid cancers. Here, we review and compare the successes and challenges of these two types of immunotherapies, with special focus on their mechanisms, and discuss strategies to improve their efficacy against cancer.Significance: CAR and BiTE cancer therapies have generated much excitement, but although the therapies are potentially competitive, information directly comparing the two is difficult to obtain. Here, we present the fundamentals of each approach and compare the range and level of functions they can elicit from T cells, and their efficacy against cancers. Cancer Discov; 8(8); 1-11. (c)2018 AACR.

Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. michael.kershaw@petermac.org clare.slaney@petermac.org. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia

Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. michael.kershaw@petermac.org clare.slaney@petermac.org. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. (2) National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, China. (3) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. (4) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. michael.kershaw@petermac.org clare.slaney@petermac.org. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.

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A Pilot Trial of Lirilumab With or Without Azacitidine for Patients With Myelodysplastic Syndrome

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BACKGROUND: Enhancement of natural killer cell activity by blocking interactions between killer immunoglobulin (Ig)-like receptors (KIRs) and human leukocyte antigen-C (HLA-C) molecules can improve outcomes in myeloid malignancies. Lirilumab is a human IgG4 monoclonal antibody that blocks KIR/HLA-C interaction. We designed a study to evaluate the safety and efficacy of lirilumab as a single agent and in combination with azacitidine in patients with myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Adult patients with MDS who had not received previous hypomethylating agents were included. Lower-risk MDS patients received single-agent lirilumab (3 mg/kg); higher-risk patients received azacitidine (75 mg/m(2)/day for 7 days) in combination with lirilumab (3 mg/kg, on day 7), in a 28-day cycle. Responses were evaluated according to 2006 International Working Group criteria. RESULTS: A total of 10 patients including 8 with higher and 2 with lower-risk enrolled. The median age was 70 (range, 50-84) years and 4 (40%) had complex cytogenetics. Baseline molecular mutations included TP53 (n = 5), TET2 (n = 3), and NRAS (n = 2). Patients received a median of 4 (range, 2-13) and 9 (range, 5-14) cycles of treatment with azacitidine with lirilumab and single-agent lirilumab, respectively. Two patients achieved complete remission (CR), 5 marrow CR, and 3 had stable disease. The median event-free survival for the entire cohort was 8 months (95% confidence interval, 4 months to not reached), and the median overall survival has not yet been reached. Five patients experienced 8 episodes of Grade >/=3 adverse events attributable to study drug, with the most frequent being infection or neutropenic fever (75%). CONCLUSION: Lirilumab either as a single agent as well as used in combination with azacitidine has clinical activity in patients with MDS. Further studies are needed to confirm our findings.

Author Info: (1) Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX. (2) Department of Leukemia, The University of Texas M.D. Anderson Cancer

Author Info: (1) Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX. (2) Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX. (3) Department of Stem Cell Transplantation, The University of Texas M.D. Anderson Cancer Center, Houston, TX. (4) Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX. (5) Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX. (6) Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX. (7) Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX. (8) Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX. (9) Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX. (10) Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX. (11) Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX. (12) Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX. (13) Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Electronic address: ggarciam@mdanderson.org.

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