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Article ; Online: Brentuximab Vedotin-Driven Microtubule Disruption Results in Endoplasmic Reticulum Stress Leading to Immunogenic Cell Death and Antitumor Immunity.

Heiser, Ryan A / Cao, Anthony T / Zeng, Weiping / Ulrich, Michelle / Younan, Patrick / Anderson, Martha E / Trueblood, Esther S / Jonas, Mechthild / Thurman, Robert / Law, Che-Leung / Gardai, Shyra J

Molecular cancer therapeutics

2023 Volume 23, Issue 1, Page(s) 68–83

Abstract: Brentuximab vedotin, a CD30-directed antibody-drug conjugate (ADC), is approved for clinical use in multiple CD30-expressing lymphomas. The cytotoxic payload component of brentuximab vedotin is monomethyl auristatin E (MMAE), a highly potent microtubule- ... ...

Abstract	Brentuximab vedotin, a CD30-directed antibody-drug conjugate (ADC), is approved for clinical use in multiple CD30-expressing lymphomas. The cytotoxic payload component of brentuximab vedotin is monomethyl auristatin E (MMAE), a highly potent microtubule-disrupting agent. Preclinical results provided here demonstrate that treatment of cancer cells with brentuximab vedotin or free MMAE leads to a catastrophic disruption of the microtubule network eliciting a robust endoplasmic reticulum (ER) stress response that culminates in the induction of the classic hallmarks of immunogenic cell death (ICD). In accordance with the induction of ICD, brentuximab vedotin-killed lymphoma cells drove innate immune cell activation in vitro and in vivo. In the "gold-standard" test of ICD, vaccination of mice with brentuximab vedotin or free MMAE-killed tumor cells protected animals from tumor rechallenge; in addition, T cells transferred from previously vaccinated animals slowed tumor growth in immunodeficient mice. Immunity acquired from killed tumor cell vaccination was further amplified by the addition of PD-1 blockade. In a humanized model of CD30+ B-cell tumors, treatment with brentuximab vedotin drove the expansion and recruitment of autologous Epstein-Barr virus-reactive CD8+ T cells potentiating the activity of anti-PD-1 therapy. Together, these data support the ability of brentuximab vedotin and MMAE to drive ICD in tumor cells resulting in the activation of antigen-presenting cells and augmented T-cell immunity. These data provide a strong rationale for the clinical combination of brentuximab vedotin and other MMAE-based ADCs with checkpoint inhibitors.
MeSH term(s)	Animals ; Mice ; Brentuximab Vedotin ; Immunogenic Cell Death ; Epstein-Barr Virus Infections ; Ki-1 Antigen ; Herpesvirus 4, Human/metabolism ; Immunoconjugates/therapeutic use ; Microtubules/metabolism
Chemical Substances	Brentuximab Vedotin (7XL5ISS668) ; Ki-1 Antigen ; Immunoconjugates
Language	English
Publishing date	2023-09-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-23-0118
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Article: Therapeutic interventions targeting CD40L (CD154) and CD40: the opportunities and challenges.

Law, Che-Leung / Grewal, Iqbal S

Advances in experimental medicine and biology

2009 Volume 647, Page(s) 8–36

Abstract: CD40 was originally identified as a receptor on B-cells that delivers contact-dependent T helper signals to B-cells through interaction with CD40 ligand (CD40L, CD154). The pivotal role played by CD40-CD40L interaction is illustrated by the defects in B- ... ...

Abstract	CD40 was originally identified as a receptor on B-cells that delivers contact-dependent T helper signals to B-cells through interaction with CD40 ligand (CD40L, CD154). The pivotal role played by CD40-CD40L interaction is illustrated by the defects in B-lineage cell development and the altered structures of secondary lymphoid tissues in patients and engineered mice deficient in CD40 or CD40L. CD40 signaling also provides critical functions in stimulating antigen presentation, priming of helper and cytotoxic T-cells and a variety of inflammatory reactions. As such, dysregulations in the CD40-CD40L costimulation pathway are prominently featured in human diseases ranging from inflammatory conditions to systemic autoimmunity and tissue-specific autoimmune diseases. Moreover, studies in CD40-expressing cancers have provided convincing evidence that the CD40-CD40L pathway regulates survival of neoplastic cells as well as presentation of tumor-associated antigens to the immune system. Extensive research has been devoted to explore CD40 and CD40L as drug targets. A number of anti-CD40L and anti-CD40 antibodies with diverse biological effects are in clinical development for treatment of cancer and autoimmune diseases. This chapter reviews the role of CD40-CD40L costimulation in disease pathogenesis, the characteristics of therapeutic agents targeting this pathway and status of their clinical development.
MeSH term(s)	Animals ; Antibodies, Monoclonal/therapeutic use ; Autoimmune Diseases/immunology ; Autoimmune Diseases/therapy ; CD40 Antigens/immunology ; CD40 Ligand/immunology ; Humans ; Mice ; Neoplasms/immunology ; Neoplasms/therapy
Chemical Substances	Antibodies, Monoclonal ; CD40 Antigens ; CD40 Ligand (147205-72-9)
Language	English
Publishing date	2009
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-0-387-89520-8_2
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Article ; Online: HPN328, a Trispecific T Cell-activating Protein Construct Targeting DLL3-Expressing Solid Tumors.

Molloy, Mary Ellen / Aaron, Wade H / Barath, Manasi / Bush, Mabel C / Callihan, Evan C / Carlin, Kevin / Cremin, Michael / Evans, Thomas / Gamez Guerrero, Maria / Hemmati, Golzar / Hundal, Avneel S / Lao, Llewelyn / Laurie, Payton / Lemon, Bryan D / Lin, S Jack / O'Rear, Jessica / Patnaik, Purbasa / Sotelo Rocha, Sony / Santiago, Linda /

Strobel, Kathryn L / Valenzuela, Laura B / Wu, Chi-Heng / Yu, Stephen / Yu, Timothy Z / Anand, Banmeet S / Law, Che-Leung / Sun, Liping L / Wesche, Holger / Austin, Richard J

Molecular cancer therapeutics

2024

Abstract: Delta-like ligand 3 (DLL3) is expressed in more than 70% of small cell lung cancers (SCLCs) and other neuroendocrine-derived tumor types. SCLC is highly aggressive and limited therapeutic options lead to poor prognosis for patients. HPN328 is a tri- ... ...

Abstract	Delta-like ligand 3 (DLL3) is expressed in more than 70% of small cell lung cancers (SCLCs) and other neuroendocrine-derived tumor types. SCLC is highly aggressive and limited therapeutic options lead to poor prognosis for patients. HPN328 is a tri-specific T cell activating construct (TriTAC) consisting of three binding domains: a CD3 binder for T cell engagement, an albumin binder for half-life extension, and a DLL3 binder for tumor cell engagement. In vitro assays, rodent models and non-human primates were used to assess the activity of HPN328. HPN328 induces potent dose-dependent killing of DLL3-expressing SCLC cell lines in vitro concomitant with T cell activation and cytokine release. In an NCI-H82 xenograft model with established tumors, HPN328 treatment led to T cell recruitment and anti-tumor activity. In an immunocompetent mouse model expressing a human CD3ε epitope, mice previously treated with HPN328 withstood tumor rechallenge, demonstrating long-term anti-tumor immunity. When repeat doses were administered to cynomolgus monkeys, HPN328 was well tolerated up to 10 mg/kg. Pharmacodynamic changes, such as transient cytokine elevation, were observed, consistent with the expected mechanism of action of T cell engagers. HPN328 exhibited linear pharmacokinetic in the given dose range with a serum half-life of 78 to 187 hours, supporting weekly or less frequent administration of HPN328 in humans. Preclinical and nonclinical characterization suggests that HPN328 is a highly efficacious, safe, and novel therapeutic candidate. A phase 1/2 clinical trial is currently underway testing safety and efficacy in patients with DLL3 expressing malignancies.
Language	English
Publishing date	2024-04-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-23-0524
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Tumor-Associated Macrophages Can Contribute to Antitumor Activity through FcγR-Mediated Processing of Antibody-Drug Conjugates.

Li, Fu / Ulrich, Michelle / Jonas, Mechthild / Stone, Ivan J / Linares, Germein / Zhang, Xinqun / Westendorf, Lori / Benjamin, Dennis R / Law, Che-Leung

Molecular cancer therapeutics

2017 Volume 16, Issue 7, Page(s) 1347–1354

Abstract: The primary mechanism of antibody-drug conjugates (ADC) is targeted delivery of a cytotoxic payload to tumor cells via cancer-associated membrane receptors. However, the tumor microenvironment likely plays a role in ADC penetration, distribution, and ... ...

Abstract	The primary mechanism of antibody-drug conjugates (ADC) is targeted delivery of a cytotoxic payload to tumor cells via cancer-associated membrane receptors. However, the tumor microenvironment likely plays a role in ADC penetration, distribution, and processing and thus impacts the overall antitumor activity. Here, we report on the potential contribution of Fc-FcγR interactions between ADCs and tumor-associated macrophages (TAM) to the preclinical antitumor activities of ADCs. In the CD30
MeSH term(s)	Animals ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/immunology ; Cell Line, Tumor ; Hodgkin Disease/drug therapy ; Hodgkin Disease/immunology ; Hodgkin Disease/pathology ; Humans ; Immunoconjugates/administration & dosage ; Immunoconjugates/immunology ; Macrophages/immunology ; Mice ; Receptors, IgG/immunology ; Tumor Microenvironment/immunology ; Xenograft Model Antitumor Assays
Chemical Substances	Antibodies, Monoclonal ; Immunoconjugates ; Receptors, IgG
Language	English
Publishing date	2017-03-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-17-0019
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Article ; Online: Preclinical Characterization of HPN536, a Trispecific, T-Cell-Activating Protein Construct for the Treatment of Mesothelin-Expressing Solid Tumors.

Molloy, Mary Ellen / Austin, Richard J / Lemon, Bryan D / Aaron, Wade H / Ganti, Vaishnavi / Jones, Adrie / Jones, Susan D / Strobel, Kathryn L / Patnaik, Purbasa / Sexton, Kenneth / Tatalick, Laurie / Yu, Timothy Z / Baeuerle, Patrick A / Law, Che-Leung / Wesche, Holger

Clinical cancer research : an official journal of the American Association for Cancer Research

2020 Volume 27, Issue 5, Page(s) 1452–1462

Abstract: Purpose: Mesothelin (MSLN) is a glycophosphatidylinositol-linked tumor antigen overexpressed in a variety of malignancies, including ovarian, pancreatic, lung, and triple-negative breast cancer. Early signs of clinical efficacy with MSLN-targeting ... ...

Abstract	Purpose: Mesothelin (MSLN) is a glycophosphatidylinositol-linked tumor antigen overexpressed in a variety of malignancies, including ovarian, pancreatic, lung, and triple-negative breast cancer. Early signs of clinical efficacy with MSLN-targeting agents have validated MSLN as a promising target for therapeutic intervention, but therapies with improved efficacy are still needed to address the significant unmet medical need posed by MSLN-expressing cancers. Experimental design: We designed HPN536, a 53-kDa, trispecific, T-cell-activating protein-based construct, which binds to MSLN-expressing tumor cells, CD3ε on T cells, and to serum albumin. Experiments were conducted to assess the potency, activity, and half-life of HPN536 in Results: HPN536 binds to MSLN-expressing tumor cells and to CD3ε on T cells, leading to T-cell activation and potent redirected target cell lysis. A third domain of HPN536 binds to serum albumin for extension of plasma half-life. In cynomolgus monkeys, HPN536 at doses ranging from 0.1 to 10 mg/kg demonstrated MSLN-dependent pharmacologic activity, was well tolerated, and showed pharmacokinetics in support of weekly dosing in humans. Conclusions: HPN536 is potent, is well tolerated, and exhibits extended half-life in NHPs. It is currently in phase I clinical testing in patients with MSLN-expressing malignancies (NCT03872206).
MeSH term(s)	Animals ; Antigens, Neoplasm/immunology ; Apoptosis ; Cell Proliferation ; Female ; Humans ; Immunotherapy/methods ; Lymphocyte Activation/immunology ; Macaca fascicularis ; Male ; Mesothelin/antagonists & inhibitors ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Neoplasms/drug therapy ; Neoplasms/immunology ; Neoplasms/metabolism ; Neoplasms/pathology ; Peptide Fragments/immunology ; Single-Domain Antibodies/immunology ; Single-Domain Antibodies/pharmacology ; T-Lymphocytes/immunology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
Chemical Substances	Antigens, Neoplasm ; MSLN protein, human ; Peptide Fragments ; Single-Domain Antibodies ; Mesothelin (J27WDC343N)
Language	English
Publishing date	2020-12-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-20-3392
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Article: Novel antibody-based therapeutic agents targeting CD70: a potential approach for treating Waldenström's macroglobulinemia.

Law, Che-Leung / McEarchern, Julie A / Grewal, Iqbal S

Clinical lymphoma & myeloma

2009 Volume 9, Issue 1, Page(s) 90–93

Abstract: Targeting leukocyte differentiation antigens is a validated approach to develop therapeutic agents for the treatment of cancer, autoimmunity, and inflammatory diseases. A subset of activation antigens transiently induced on leukocytes is particularly ... ...

Abstract	Targeting leukocyte differentiation antigens is a validated approach to develop therapeutic agents for the treatment of cancer, autoimmunity, and inflammatory diseases. A subset of activation antigens transiently induced on leukocytes is particularly interesting because many of them are absent from normal tissues, including those of most vital organs, and therapeutic agents' targeting of such antigens is expected to impart limited toxicity. One such antigen, CD70, has recently emerged as an attractive potential drug target for the treatment of cancers. Whereas CD70 is only transiently expressed on activation T and B cells and mature dendritic cells, it is found to be aberrantly expressed on a variety of tumor cells, including Waldenström's macroglobulinemia. In this report, we discuss potential antibody-based therapeutic approaches targeting CD70 for tumor elimination where various mechanisms such as antibody effector functions, immune enhancement, blockade of paracrine growth loop, and delivery of cytotoxic payloads can be exploited to achieve efficacy. Indeed, early clinical trials with therapeutic anti-CD70 antibodies are currently in progress, and those for anti-CD70 drug conjugates will soon follow.
MeSH term(s)	Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/therapeutic use ; CD27 Ligand/antagonists & inhibitors ; CD27 Ligand/immunology ; Humans ; Waldenstrom Macroglobulinemia/drug therapy ; Waldenstrom Macroglobulinemia/immunology
Chemical Substances	Antibodies, Monoclonal ; CD27 Ligand
Language	English
Publishing date	2009-03
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2228154-X
ISSN	1557-9190
ISSN	1557-9190
DOI	10.3816/CLM.2009.n.024
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: TriTACs, a Novel Class of T-Cell-Engaging Protein Constructs Designed for the Treatment of Solid Tumors.

Molecular cancer therapeutics

2020 Volume 20, Issue 1, Page(s) 109–120

Abstract: T cells have a unique capability to eliminate cancer cells and fight malignancies. Cancer cells have adopted multiple immune evasion mechanisms aimed at inhibiting T cells. Dramatically improved patient outcomes have been achieved with therapies ... ...

Abstract	T cells have a unique capability to eliminate cancer cells and fight malignancies. Cancer cells have adopted multiple immune evasion mechanisms aimed at inhibiting T cells. Dramatically improved patient outcomes have been achieved with therapies genetically reprogramming T cells, blocking T-cell inhibition by cancer cells, or transiently connecting T cells with cancer cells for redirected lysis. This last modality is based on antibody constructs that bind a surface antigen on cancer cells and an invariant component of the T-cell receptor. Although high response rates were observed with T-cell engagers specific for CD19, CD20, or BCMA in patients with hematologic cancers, the treatment of solid tumors has been less successful. Here, we developed and characterized a novel T-cell engager format, called TriTAC (for Trispecific T-cell Activating Construct). TriTACs are engineered with features to improve patient safety and solid tumor activity, including high stability, small size, flexible linkers, long serum half-life, and highly specific and potent redirected lysis. The present study establishes the structure/activity relationship of TriTACs and describes the development of HPN424, a PSMA- (FOLH1-) targeting TriTAC in clinical development for patients with metastatic castration-resistant prostate cancer.
MeSH term(s)	Albumins/pharmacology ; Animals ; Antineoplastic Agents/blood ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; CD3 Complex/metabolism ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Half-Life ; Humans ; Lymphocyte Activation/drug effects ; Lymphocyte Activation/immunology ; Macaca fascicularis ; Mice, Inbred NOD ; Mice, SCID ; Neoplasms/drug therapy ; Neoplasms/pathology ; Prostate-Specific Antigen/metabolism ; T-Lymphocytes/drug effects ; T-Lymphocytes/metabolism ; Mice
Chemical Substances	Albumins ; Antineoplastic Agents ; CD3 Complex ; Prostate-Specific Antigen (EC 3.4.21.77)
Language	English
Publishing date	2020-11-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-20-0061
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Intracellular Released Payload Influences Potency and Bystander-Killing Effects of Antibody-Drug Conjugates in Preclinical Models.

Li, Fu / Emmerton, Kim K / Jonas, Mechthild / Zhang, Xinqun / Miyamoto, Jamie B / Setter, Jocelyn R / Nicholas, Nicole D / Okeley, Nicole M / Lyon, Robert P / Benjamin, Dennis R / Law, Che-Leung

Cancer research

2016 Volume 76, Issue 9, Page(s) 2710–2719

Abstract: Antibody-drug conjugates (ADC) comprise targeting antibodies armed with potent small-molecule payloads. ADCs demonstrate specific cell killing in clinic, but the basis of their antitumor activity is not fully understood. In this study, we investigated ... ...

Abstract	Antibody-drug conjugates (ADC) comprise targeting antibodies armed with potent small-molecule payloads. ADCs demonstrate specific cell killing in clinic, but the basis of their antitumor activity is not fully understood. In this study, we investigated the degree to which payload release predicts ADC activity in vitro and in vivo ADCs were generated to target different receptors on the anaplastic large cell lymphoma line L-82, but delivered the same cytotoxic payload (monomethyl auristatin E, MMAE), and we found that the intracellular concentration of released MMAE correlated with in vitro ADC-mediated cytotoxicity independent of target expression or drug:antibody ratios. Intratumoral MMAE concentrations consistently correlated with the extent of tumor growth inhibition in tumor xenograft models. In addition, we developed a robust admixed tumor model consisting of CD30(+) and CD30(-) cancer cells to study how heterogeneity of target antigen expression, a phenomenon often observed in cancer specimens, affects the treatment response. CD30-targeting ADC delivering membrane permeable MMAE or pyrrolobenzodiazepine dimers demonstrated potent bystander killing of neighboring CD30(-) cells. In contrast, a less membrane permeable payload, MMAF, failed to mediate bystander killing in vivo, suggesting local diffusion and distribution of released payloads represents a potential mechanism of ADC-mediated bystander killing. Collectively, our findings establish that the biophysical properties and amount of released payloads are chief factors determining the overall ADC potency and bystander killing. Cancer Res; 76(9); 2710-9. ©2016 AACR.
MeSH term(s)	Animals ; Antibodies, Monoclonal/pharmacology ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Chromatography, Liquid ; Drug Delivery Systems/methods ; Flow Cytometry ; Humans ; Immunoconjugates/pharmacology ; Immunohistochemistry ; Lymphoma/pathology ; Mass Spectrometry ; Mice ; Mice, SCID ; Oligopeptides/pharmacology ; Xenograft Model Antitumor Assays
Chemical Substances	Antibodies, Monoclonal ; Antineoplastic Agents ; Immunoconjugates ; Oligopeptides ; monomethyl auristatin E (V7I58RC5EJ)
Language	English
Publishing date	2016--01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-15-1795
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Targeting CD70 for human therapeutic use.

Boursalian, Tamar E / McEarchern, Julie A / Law, Che-Leung / Grewal, Iqbal S

Advances in experimental medicine and biology

2009 Volume 647, Page(s) 108–119

Abstract: Expression of CD70, a member of the tumor necrosis factor superfamily, is restricted to activated T-and B-lymphocytes and mature dendritic cells. Binding of CD70 to its receptor, CD27, is important in priming, effector functions, differentiation and ... ...

Abstract	Expression of CD70, a member of the tumor necrosis factor superfamily, is restricted to activated T-and B-lymphocytes and mature dendritic cells. Binding of CD70 to its receptor, CD27, is important in priming, effector functions, differentiation and memory formation of T-cells as well as plasma and memory B-cell generation. Antibody blockade of CD70-CD27 interaction inhibits the onset of experimental autoimmune encephalomyelits and cardiac allograft rejection in mice. CD70 has been also detected on hematological tumors and on carcinomas. The highly restricted expression pattern of CD70 in normal tissues and its widespread expression in various malignancies as well as its potential role in autoimmune and inflammatory conditions makes it an attractive target for antibody-based therapeutics. This chapter provides an overview of the physiological role of CD70-CD27 interactions and discusses various approaches to target this pathway for therapeutic use in cancers and autoimmunity.
MeSH term(s)	Animals ; Autoimmune Diseases/metabolism ; Autoimmune Diseases/therapy ; CD27 Ligand/antagonists & inhibitors ; CD27 Ligand/metabolism ; Humans ; Mice ; Neoplasms/therapy ; Tumor Necrosis Factor Receptor Superfamily, Member 7/antagonists & inhibitors ; Tumor Necrosis Factor Receptor Superfamily, Member 7/metabolism
Chemical Substances	CD27 Ligand ; Tumor Necrosis Factor Receptor Superfamily, Member 7
Language	English
Publishing date	2009
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-0-387-89520-8_7
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: 5-azacytidine enhances the anti-leukemic activity of lintuzumab (SGN-33) in preclinical models of acute myeloid leukemia.

Sutherland, May Kung / Yu, Changpu / Anderson, Martha / Zeng, Weiping / van Rooijen, Nico / Sievers, Eric L / Grewal, Iqbal S / Law, Che-Leung

mAbs

2010 Volume 2, Issue 4, Page(s) 440–448

Abstract: Despite therapeutic advances, the poor prognoses for acute myeloid leukemia (AML) and intermediate and high-risk myelodysplastic syndromes (MDS) point to the need for better treatment options. AML and MDS cells express the myeloid marker CD33, making it ... ...

Abstract	Despite therapeutic advances, the poor prognoses for acute myeloid leukemia (AML) and intermediate and high-risk myelodysplastic syndromes (MDS) point to the need for better treatment options. AML and MDS cells express the myeloid marker CD33, making it amenable to CD33-targeted therapy. Lintuzumab (SGN-33), a humanized monoclonal anti-CD33 antibody undergoing clinical evaluation, induced meaningful responses in a Phase 1 clinical trial and demonstrated anti-leukemic activity in preclinical models. Recently, it was reported that 5-azacytidine (Vidaza™) prolonged the overall survival of a group of high risk MDS and AML patients. To determine whether the combination of lintuzumab and 5-azacytidine would be beneficial, a mouse xenograft model of disseminated AML was used to evaluate the combination. There was a significant reduction in tumor burden and an increase in overall survival in mice treated with lintuzumab and 5-azacytidine. The effects were greater than that obtained with either agent alone. As the in vivo anti-leukemic activity of lintuzumab was dependent upon the presence of mouse effector cells including macrophages and neutrophils, in vitro effector function assays were used to assess the impact of 5-azacytidine on lintuzumab activity. The results show that 5-azacytidine significantly enhanced the ability of lintuzumab to promote tumor cell killing through antibody-dependent cellular cytotoxicity (ADCC) and phagocytic (ADCP) activities. These results suggest that lintuzumab and 5-azacytidine act in concert to promote tumor cell killing. Additionally, these findings provide the rationale to evaluate this combination in the clinic.
MeSH term(s)	Animals ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibody-Dependent Cell Cytotoxicity/drug effects ; Antineoplastic Agents/administration & dosage ; Azacitidine/administration & dosage ; Drug Evaluation, Preclinical ; Drug Synergism ; Drug Therapy, Combination ; HL-60 Cells ; Humans ; Leukemia, Myeloid, Acute/immunology ; Leukemia, Myeloid, Acute/therapy ; Macrophages/drug effects ; Macrophages/immunology ; Mice ; Mice, SCID ; Neutrophils/drug effects ; Neutrophils/immunology ; Phagocytosis/drug effects ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays
Chemical Substances	Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; Azacitidine (M801H13NRU) ; lintuzumab (V00Y10W60W)
Language	English
Publishing date	2010-07-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2537838-7
ISSN	1942-0870 ; 1942-0870
ISSN (online)	1942-0870
ISSN	1942-0870
DOI	10.4161/mabs.12203
Database	MEDical Literature Analysis and Retrieval System OnLINE

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