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Article ; Online: Evolution of anti-CD20 monoclonal antibody therapeutics in oncology.

Oflazoglu, Ezogelin / Audoly, Laurent P

2010 Volume 2, Issue 1, Page(s) 14–19

Abstract: Approval of an anti-CD20 chimeric monoclonal antibody, rituximab, has revolutionized cancer treatment and also validated CD20 targeting for providing benefit and improvement of overall response rate in B cell malignancies. Although many patients have ... ...

Abstract	Approval of an anti-CD20 chimeric monoclonal antibody, rituximab, has revolutionized cancer treatment and also validated CD20 targeting for providing benefit and improvement of overall response rate in B cell malignancies. Although many patients have benefited from the treatment of rituximab, there are still significant numbers of patients who are refractory or develop resistance to the treatment. Here we discuss pre-clinically well-defined potential mechanisms of action for rituximab and review the ways next generation anti-CD20 monoclonal antibodies can potentially exploit them to further enhance the treatment of B cell malignancies. Although the relative importance of each of these mechanism remains to be established in the clinic, well-designed clinical trials will help to define the efficacy and understanding of which effector activity of modified next generation anti-CD20 mAb will be important in the treatment of B-cell malignancies.
MeSH term(s)	Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal/therapeutic use ; Antibodies, Monoclonal, Murine-Derived ; Apoptosis/immunology ; B-Lymphocytes/drug effects ; B-Lymphocytes/immunology ; Clinical Trials as Topic ; Drug Resistance, Neoplasm ; Humans ; Immunotherapy ; Lymphoma, B-Cell/drug therapy ; Lymphoma, B-Cell/immunology ; Medical Oncology ; Rituximab ; Signal Transduction/immunology
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Monoclonal, Murine-Derived ; Rituximab (4F4X42SYQ6)
Language	English
Publishing date	2010-01-30
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2537838-7
ISSN	1942-0870 ; 1942-0870
ISSN (online)	1942-0870
ISSN	1942-0870
DOI	10.4161/mabs.2.1.10789
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Targeting CD30/CD30L in oncology and autoimmune and inflammatory diseases.

Oflazoglu, Ezogelin / Grewal, Iqbal S / Gerber, Hanspeter

Advances in experimental medicine and biology

2009 Volume 647, Page(s) 174–185

Abstract: The transmembrane receptor CD30 (TNFRSF8) and its ligand CD30L (CD153, TNFSF8) are members of the tumor necrosis factor (TNF) superfamily and display restricted expression in subpopulations of activated T-and B-cells in nonpathologic conditions. CD30 ... ...

Abstract	The transmembrane receptor CD30 (TNFRSF8) and its ligand CD30L (CD153, TNFSF8) are members of the tumor necrosis factor (TNF) superfamily and display restricted expression in subpopulations of activated T-and B-cells in nonpathologic conditions. CD30 expression is upregulated in various hematological malignancies, including Reed-Sternberg cells in Hodgkin's disease (HD), anaplastic large cell lymphoma (ALCL) and subsets of Non-Hodgkin's lymphomas (NHLs). Increased CD30L expression was found on mast cells within HD tumors and preclinical and clinical studies with compounds targeting the CD30/ CD30L system in HD and ALCL demonstrated therapeutic benefit. Upregulation of CD30 and CD30L is also linked to leukocytes in patients with chronic inflammatory diseases, including lupus erythematosus, asthma, rheumatoid arthritis and atopic dermatitis (AD). Preclinical studies conducted with transgenic mice or biologic compounds suggested important regulatory functions of the CD30-CD30L system in various aspects of the immune system. Such key regulatory roles and their low expression in normal conditions combined with increased expression in malignant tissues provided a strong rationale to investigate CD30 and CD30L as therapeutic targets in hematologic malignancies, autoimmune and inflammatory diseases. In this report, we review the pharmacodynamic effects of specific therapeutic compounds targeting the CD30/CD30L system in preclinical- and clinical studies.
MeSH term(s)	Animals ; Autoimmune Diseases/immunology ; Autoimmune Diseases/therapy ; CD30 Ligand/antagonists & inhibitors ; CD30 Ligand/metabolism ; Humans ; Inflammation/immunology ; Inflammation/therapy ; Ki-1 Antigen/antagonists & inhibitors ; Ki-1 Antigen/metabolism ; Mice ; Neoplasms/immunology ; Neoplasms/therapy
Chemical Substances	CD30 Ligand ; Ki-1 Antigen
Language	English
Publishing date	2009
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-0-387-89520-8_12
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Article ; Online: Susceptibility of human T-cell leukemia virus type I-infected cells to humanized anti-CD30 monoclonal antibodies in vitro and in vivo.

Maeda, Naoyoshi / Muta, Hiromi / Oflazoglu, Ezogelin / Yoshikai, Yasunobu

Cancer science

2009 Volume 101, Issue 1, Page(s) 224–230

Abstract: Adult T-cell leukemia (ATL) is an aggressive malignancy of activated CD4(+) T cells associated with human T-cell leukemia virus type I (HTLV-I) infection. No conventional chemotherapy regimen has appeared successful in patients with ATL, thus ... ...

Abstract	Adult T-cell leukemia (ATL) is an aggressive malignancy of activated CD4(+) T cells associated with human T-cell leukemia virus type I (HTLV-I) infection. No conventional chemotherapy regimen has appeared successful in patients with ATL, thus establishing effective therapy is urgently required. In some cases, ATL tumor cells express CD30 on the cell surface, therefore, a therapy with mAb against CD30 would be beneficial. To investigate the effect of CD30-mediated therapy on ATL, we assessed SGN-30, a chimeric anti-CD30 mAb, and SGN-35, a monomethyl auristatin E-conjugated anti-CD30 mAb, in vitro and in vivo. Three HTLV-I-infected cell lines were co-cultured with SGN-30 or SGN-35, and the growth-inhibitory effects on the HTLV-I-infected cells were evaluated using an in vitro cell proliferation assay and cell cycle analysis. SGN-30 and SGN-35 showed growth-inhibitory activity against the HTLV-I-infected cell lines by apoptosis and/or cell growth arrest in vitro. To further investigate the effects of SGN-30 and SGN-35 on HTLV-I-infected cells in vivo, we used NOD/SCID mice subcutaneously engrafted with HTLV-I-infected cells. Both mAbs significantly inhibited the growth of HTLV-I-infected cell tumors in the NOD/SCID murine xenograft models. These data suggest that CD30-mediated therapy with SGN-30 or SGN-35 would be useful for patients with ATL.
MeSH term(s)	Animals ; Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal/therapeutic use ; Cell Line, Tumor ; HTLV-I Infections/drug therapy ; Humans ; Ki-1 Antigen/immunology ; Leukemia-Lymphoma, Adult T-Cell/drug therapy ; Mice
Chemical Substances	Antibodies, Monoclonal ; Ki-1 Antigen ; SGN-30 monoclonal antibody (C67ORA155P)
Language	English
Publishing date	2009-09-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1349-7006
ISSN (online)	1349-7006
DOI	10.1111/j.1349-7006.2009.01354.x
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Article: CD40 expression on antigen presenting cells and correlation with disease severity in atopic dermatitis.

Oflazoglu, Ezogelin / Simpson, Eric L / Takiguchi, Rodd / Hanifin, Jon M / Grewal, Iqbal S / Gerber, Hans-Peter

European journal of dermatology : EJD

2008 Volume 18, Issue 5, Page(s) 527–533

Abstract: Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with cutaneous hyperreactivity to environmental stimuli, resulting in increased infiltration of inflammatory cells, IgE production and enhanced expression of various co-stimulatory ... ...

Abstract	Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with cutaneous hyperreactivity to environmental stimuli, resulting in increased infiltration of inflammatory cells, IgE production and enhanced expression of various co-stimulatory molecules, Th2 cytokines and chemokines. Antigen presenting cells (APCs) are critical for AD disease pathogenesis and interaction between APCs and inflammatory T cells represents an important signal required for induction and maintenance of the inflammatory process. CD40 was shown to be upregulated on inflammatory cells in patients with atopic dermatitis; however the identity of these cells and their correlation with disease severity remained unknown. To address these questions, we determined CD40 expression in skin lesions and on peripheral blood cells from AD patients and identified a positive correlation between the numbers of CD40 positive cells and disease severity. Furthermore, we identified the nature of CD40 positive cells in skin lesions to include CD1a+ and CD11b+ APCs. Finally, a correlation between serum PARC and IgE levels and the numbers of CD40+ cells in AD skin lesions was found. Combined, these findings demonstrate that CD40 is upregulated on APCs, cell types previously shown to contribute to AD disease pathology, and suggest that therapeutic strategies targeting CD40 positive cells may provide benefit to AD patients.
MeSH term(s)	Antigen-Presenting Cells/immunology ; CD40 Antigens/biosynthesis ; Dermatitis, Atopic/immunology ; Humans ; Severity of Illness Index
Chemical Substances	CD40 Antigens
Language	English
Publishing date	2008-09
Publishing country	France
Document type	Comparative Study ; Journal Article
ZDB-ID	1128666-0
ISSN	1952-4013 ; 1167-1122
ISSN (online)	1952-4013
ISSN	1167-1122
DOI	10.1684/ejd.2008.0495
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Article ; Online: Combination of the anti-CD30-auristatin-E antibody-drug conjugate (SGN-35) with chemotherapy improves antitumour activity in Hodgkin lymphoma.

Oflazoglu, Ezogelin / Kissler, Kim M / Sievers, Eric L / Grewal, Iqbal S / Gerber, Hans-Peter

British journal of haematology

2008 Volume 142, Issue 1, Page(s) 69–73

Abstract: The antibody-drug conjugate (ADC) cAC10-vcMMAE consists of the tubulin inhibitor monomethyl auristatin E (MMAE) conjugated to the chimeric anti-CD30 monoclonal antibody cAC10. This ADC potently interferes with the growth of CD30-positive haematological ... ...

Abstract	The antibody-drug conjugate (ADC) cAC10-vcMMAE consists of the tubulin inhibitor monomethyl auristatin E (MMAE) conjugated to the chimeric anti-CD30 monoclonal antibody cAC10. This ADC potently interferes with the growth of CD30-positive haematological tumours, including Hodgkin lymphoma (HL) and anaplastic large-cell lymphoma. This study found improved antitumour activity in a preclinical model of HL when SGN-35 was combined with chemotherapeutic regimens such as ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) or gemcitabine. Improved efficacy was also observed in high tumour burden models, indicating that combining ADCs with chemotherapeutic agents may be advantageous for the treatment of patients with relapsed or refractory HL.
MeSH term(s)	Animals ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Bleomycin/administration & dosage ; Dacarbazine/administration & dosage ; Deoxycytidine/administration & dosage ; Deoxycytidine/analogs & derivatives ; Doxorubicin/administration & dosage ; Hodgkin Disease/therapy ; Immunoconjugates/administration & dosage ; Ki-1 Antigen/administration & dosage ; Mice ; Mice, SCID ; Neoplasm Transplantation ; Oligopeptides/administration & dosage ; Tubulin Modulators/administration & dosage ; Vinblastine/administration & dosage
Chemical Substances	Immunoconjugates ; Ki-1 Antigen ; Oligopeptides ; Tubulin Modulators ; Deoxycytidine (0W860991D6) ; Bleomycin (11056-06-7) ; Vinblastine (5V9KLZ54CY) ; Dacarbazine (7GR28W0FJI) ; Doxorubicin (80168379AG) ; gemcitabine (B76N6SBZ8R) ; monomethyl auristatin E (V7I58RC5EJ)
Language	English
Publishing date	2008-05-08
Publishing country	England
Document type	Journal Article
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1111/j.1365-2141.2008.07146.x
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Article: CD30 expression on CD1a+ and CD8+ cells in atopic dermatitis and correlation with disease severity.

Oflazoglu, Ezogelin / Simpson, Eric L / Takiguchi, Rodd / Grewal, Iqbal S / Hanifin, Jon M / Gerber, Hans-Peter

European journal of dermatology : EJD

2008 Volume 18, Issue 1, Page(s) 41–49

Abstract	Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with cutaneous hyperreactivity to environmental stimuli, resulting in increased infiltration of inflammatory cells, IgE production and enhanced expression of costimulatory molecules, cytokines and chemokines. CD30, a TNF receptor superfamily member, is a costimulatory molecule expressed on activated T and B cells. A positive correlation between soluble CD30 (sCD30) levels in patient serum and AD disease severity has been described previously. However, the relative frequencies and identities of cells expressing CD30 in AD patients and the relationship between the frequency of CD30 positive cells and serum sCD30 levels with disease severity remained unknown. To address these questions, immunofluorescence analysis of AD skin lesions representing different disease stages, was conducted. In addition to the CD4+ T cells, CD1a+ Langerhans cells and CD8+ T cells were found to express CD30 in AD lesions and the cell numbers correlated with disease severity. FACS analysis of AD patient blood samples revealed expression of CD30 on memory T-cells and a correlation with disease severity was identified. Finally, serum analysis of soluble mediators revealed positive correlations between sCD30, IgE, MDC, TARC and PARC levels with disease severity. Combined, our data provide correlative evidence that CD30+ cells, including Langerhans cells and CD8+ T-cells, may contribute to AD disease severity and that therapeutic strategies targeting CD30+ cells may provide benefit to AD patients.
MeSH term(s)	Antigens, CD1/analysis ; CD4 Antigens/analysis ; CD8-Positive T-Lymphocytes/immunology ; Chemokine CCL17/blood ; Chemokines, CC/blood ; Dermatitis, Atopic/immunology ; Dermatitis, Atopic/pathology ; Humans ; Immunohistochemistry ; Interleukin-8/blood ; Ki-1 Antigen/analysis ; Ki-1 Antigen/blood ; Langerhans Cells/immunology ; Skin/immunology ; Skin/pathology
Chemical Substances	Antigens, CD1 ; CCL18 protein, human ; CD1a antigen ; CD4 Antigens ; Chemokine CCL17 ; Chemokines, CC ; Interleukin-8 ; Ki-1 Antigen
Language	English
Publishing date	2008-01
Publishing country	France
Document type	Journal Article
ZDB-ID	1128666-0
ISSN	1952-4013 ; 1167-1122
ISSN (online)	1952-4013
ISSN	1167-1122
DOI	10.1684/ejd.2008.0309
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Article ; Online: Adoptively transferred human lung tumor specific cytotoxic T cells can control autologous tumor growth and shape tumor phenotype in a SCID mouse xenograft model.

Oflazoglu, Ezogelin / Elliott, Mark / Takita, Hiroshi / Ferrone, Soldano / Henderson, Robert A / Repasky, Elizabeth A

Journal of translational medicine

2007 Volume 5, Page(s) 29

Abstract: Background: The anti-tumor efficacy of human immune effector cells, such as cytolytic T lymphocytes (CTLs), has been difficult to study in lung cancer patients in the clinical setting. Improved experimental models for the study of lung tumor-immune cell ...

Abstract	Background: The anti-tumor efficacy of human immune effector cells, such as cytolytic T lymphocytes (CTLs), has been difficult to study in lung cancer patients in the clinical setting. Improved experimental models for the study of lung tumor-immune cell interaction as well as for evaluating the efficacy of adoptive transfer of immune effector cells are needed. Methods: To address questions related to the in vivo interaction of human lung tumor cells and immune effector cells, we obtained an HLA class I (+) lung tumor cell line from a fresh surgical specimen, and using the infiltrating immune cells, isolated and characterized tumor antigen-specific, CD8(+) CTLs. We then established a SCID mouse-human tumor xenograft model with the tumor cell line and used it to study the function of the autologous CTLs provided via adoptive transfer. Results: The tumor antigen specific CTLs isolated from the tumor were found to have an activated memory phenotype and able to kill tumor cells in an antigen specific manner in vitro. Additionally, the tumor antigen-specific CTLs were fully capable of homing to and killing autologous tumors in vivo, and expressing IFN-gamma, each in an antigen-dependent manner. A single injection of these CTLs was able to provide significant but temporary control of the growth of autologous tumors in vivo without the need for IL-2. The timing of injection of CTLs played an essential role in the outcome of tumor growth control. Moreover, immunohistochemical analysis of surviving tumor cells following CTL treatment indicated that the surviving tumor cells expressed reduced MHC class I antigens on their surface. Conclusion: These studies confirm and extend previous studies and provide additional information regarding the characteristics of CTLs which can be found within a patient's tumor. Moreover, the in vivo model described here provides a unique window for observing events that may also occur in patients undergoing adoptive cellular immunotherapy as effector cells seek and destroy areas of tumor growth and for testing strategies to improve clinical effectiveness.
MeSH term(s)	Adoptive Transfer ; Animals ; Antigens, Neoplasm/immunology ; Cell Proliferation ; Cytokines/secretion ; Cytotoxicity, Immunologic ; Epitopes/immunology ; Histocompatibility Antigens Class I/immunology ; Humans ; Immunologic Memory ; Lung Neoplasms/immunology ; Lung Neoplasms/pathology ; Lymphocytes, Tumor-Infiltrating/immunology ; Male ; Mice ; Mice, SCID ; Organ Specificity ; Phenotype ; T-Lymphocytes, Cytotoxic/immunology ; Time Factors ; Xenograft Model Antitumor Assays
Chemical Substances	Antigens, Neoplasm ; Cytokines ; Epitopes ; Histocompatibility Antigens Class I
Language	English
Publishing date	2007-06-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1479-5876
ISSN (online)	1479-5876
DOI	10.1186/1479-5876-5-29
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Article: Enhancement of natural killer (NK) cell cytotoxicity by fever-range thermal stress is dependent on NKG2D function and is associated with plasma membrane NKG2D clustering and increased expression of MICA on target cells.

Ostberg, Julie R / Dayanc, Baris E / Yuan, Min / Oflazoglu, Ezogelin / Repasky, Elizabeth A

Journal of leukocyte biology

2007 Volume 82, Issue 5, Page(s) 1322–1331

Abstract: Circulating NK cells normally experience temperature gradients as they move about the body, but the onset of inflammation can expose them and their targets to febrile temperatures for several hours. We found that exposure of human peripheral blood NK ... ...

Abstract	Circulating NK cells normally experience temperature gradients as they move about the body, but the onset of inflammation can expose them and their targets to febrile temperatures for several hours. We found that exposure of human peripheral blood NK cells and target cells to fever-range temperatures significantly enhances lysis of Colo205 target cells. A similar effect was not observed when NK cell lines or IL-2-activated peripheral blood NK cells were used as effectors, indicating that thermal sensitivity of effectors is maturation or activation state-dependent. Use of blocking antibodies revealed that this effect is also dependent on the function of the activating receptor NKG2D and its ligand MHC class I-related chain A (MICA). On NK cells, it was observed that thermal exposure does not affect the total level of NKG2D surface expression, but does result in its distinct clustering, identical to that which occurs following IL-2-induced activation. On tumor target cells, a similar, mild temperature elevation results in transcriptional up-regulation of MICA in a manner that correlates with increased sensitivity to cytolysis. Overall, these data reveal that NK cells possess thermally responsive regulatory elements, which facilitate their ability to capitalize on reciprocal, stress-induced changes simultaneously occurring on target cells during inflammation and fever.
MeSH term(s)	Cell Communication ; Cell Membrane/metabolism ; Cell Survival/immunology ; Cell Survival/physiology ; Cells, Cultured ; Cytotoxicity, Immunologic ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Fluorescent Antibody Technique ; Histocompatibility Antigens Class I/genetics ; Histocompatibility Antigens Class I/metabolism ; Hot Temperature ; Humans ; Immunologic Surveillance ; Interleukin-2/metabolism ; Killer Cells, Natural/cytology ; Killer Cells, Natural/immunology ; Killer Cells, Natural/metabolism ; NK Cell Lectin-Like Receptor Subfamily K ; Neoplasms/metabolism ; Neoplasms/pathology ; Protein Transport ; Receptors, Immunologic/genetics ; Receptors, Immunologic/metabolism ; Receptors, Natural Killer Cell ; Regulatory Elements, Transcriptional ; Reverse Transcriptase Polymerase Chain Reaction
Chemical Substances	Histocompatibility Antigens Class I ; Interleukin-2 ; KLRK1 protein, human ; MHC class I-related chain A ; NK Cell Lectin-Like Receptor Subfamily K ; Receptors, Immunologic ; Receptors, Natural Killer Cell
Language	English
Publishing date	2007-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	605722-6
ISSN	1938-3673 ; 0741-5400
ISSN (online)	1938-3673
ISSN	0741-5400
DOI	10.1189/jlb.1106699
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Article ; Online: Adoptively transferred human lung tumor specific cytotoxic T cells can control autologous tumor growth and shape tumor phenotype in a SCID mouse xenograft model

Ferrone Soldano / Takita Hiroshi / Elliott Mark / Oflazoglu Ezogelin / Henderson Robert A / Repasky Elizabeth A

Journal of Translational Medicine, Vol 5, Iss 1, p

2007 Volume 29

Abstract: Abstract Background The anti-tumor efficacy of human immune effector cells, such as cytolytic T lymphocytes (CTLs), has been difficult to study in lung cancer patients in the clinical setting. Improved experimental models for the study of lung tumor- ... ...

Abstract	Abstract Background The anti-tumor efficacy of human immune effector cells, such as cytolytic T lymphocytes (CTLs), has been difficult to study in lung cancer patients in the clinical setting. Improved experimental models for the study of lung tumor-immune cell interaction as well as for evaluating the efficacy of adoptive transfer of immune effector cells are needed. Methods To address questions related to the in vivo interaction of human lung tumor cells and immune effector cells, we obtained an HLA class I + lung tumor cell line from a fresh surgical specimen, and using the infiltrating immune cells, isolated and characterized tumor antigen-specific, CD8 + CTLs. We then established a SCID mouse-human tumor xenograft model with the tumor cell line and used it to study the function of the autologous CTLs provided via adoptive transfer. Results The tumor antigen specific CTLs isolated from the tumor were found to have an activated memory phenotype and able to kill tumor cells in an antigen specific manner in vitro . Additionally, the tumor antigen-specific CTLs were fully capable of homing to and killing autologous tumors in vivo , and expressing IFN-γ, each in an antigen-dependent manner. A single injection of these CTLs was able to provide significant but temporary control of the growth of autologous tumors in vivo without the need for IL-2. The timing of injection of CTLs played an essential role in the outcome of tumor growth control. Moreover, immunohistochemical analysis of surviving tumor cells following CTL treatment indicated that the surviving tumor cells expressed reduced MHC class I antigens on their surface. Conclusion These studies confirm and extend previous studies and provide additional information regarding the characteristics of CTLs which can be found within a patient's tumor. Moreover, the in vivo model described here provides a unique window for observing events that may also occur in patients undergoing adoptive cellular immunotherapy as effector cells seek and destroy areas of tumor ...
Keywords	Medicine ; R
Subject code	610 ; 570
Language	English
Publishing date	2007-06-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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Article: Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to the tubulin inhibitor auristatin via an uncleavable linker.

Oflazoglu, Ezogelin / Stone, Ivan J / Gordon, Kristine / Wood, Christopher G / Repasky, Elizabeth A / Grewal, Iqbal S / Law, Che-Leung / Gerber, Hans-Peter

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

2008 Volume 14, Issue 19, Page(s) 6171–6180

Abstract: Purpose: The antitubulin agent monomethyl auristatin F (MMAF) induces potent antitumor effects when conjugated via protease cleavable linkers to antibodies targeting internalizing, tumor-specific cell surface antigens. Humanized 1F6 (h1F6) is a ... ...

Abstract	Purpose: The antitubulin agent monomethyl auristatin F (MMAF) induces potent antitumor effects when conjugated via protease cleavable linkers to antibodies targeting internalizing, tumor-specific cell surface antigens. Humanized 1F6 (h1F6) is a humanized monoclonal antibody targeting CD70, a member of the tumor necrosis factor family that is expressed on hematologic malignancies and carcinomas. Here, we tested h1F6-maleimidocaproyl (mc) MMAF conjugates, consisting of an uncleavable mc linker, for their ability to interfere with the growth of CD70-positive carcinomas. Experimental design: To evaluate the optimal drug per antibody ratio, we conjugated either four or eight MMAF molecules to the cysteines that comprise the interchain disulfides of h1F6 and determined antitumor activities in vitro and in xenografted mice. The tumor types tested included glioblastoma, patient-derived renal cell carcinoma (RCC) cell isolates, and standard RCC tumor cell lines. Results: All h1F6-mcMMAF conjugates potently interfered with the growth of all carcinomas in vitro and resulted in complete responses of RCC tumors implanted orthotopically or s.c. in mice. In vitro, h1F6-mcMMAF(8) was generally more potent than h1F6-mcMMAF(4). However, h1F6-mcMMAF(4) displayed equal or better efficacy than h1F6-mcMMAF(8) when administered to tumor-bearing mice. Conclusions: We showed that h1F6-mcMMAF conjugates inhibited the growth of human carcinomas and that increased drug loading, while improving potency in vitro, did not substantially affect the pharmacodynamic and pharmacokinetic properties in vivo. Based on these findings, h1F6-mcMMAF(4), designated SGN-75, has been identified as a potential antibody-drug conjugate for clinical development.
MeSH term(s)	Animals ; Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal, Humanized/chemistry ; Antibodies, Monoclonal, Humanized/pharmacology ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; CD27 Ligand/chemistry ; CD27 Ligand/immunology ; Carcinoma, Renal Cell/drug therapy ; Carcinoma, Renal Cell/pathology ; Cell Line, Tumor ; Disulfides/chemistry ; Glioblastoma/drug therapy ; Glioblastoma/pathology ; Humans ; Inhibitory Concentration 50 ; Kidney Neoplasms/drug therapy ; Kidney Neoplasms/pathology ; Mice ; Neoplasm Transplantation ; Oligopeptides/chemistry ; Oligopeptides/pharmacology ; Tubulin/chemistry ; Tubulin Modulators/chemistry
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; CD27 Ligand ; Disulfides ; Oligopeptides ; SGN-75 antibody-drug conjugate ; Tubulin ; Tubulin Modulators ; monomethylauristatin F
Language	English
Publishing date	2008-10-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-08-0916
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Inter-library loan at ZB MED

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In stock of ZB MED Cologne/Königswinter

Order via subito