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Featured researches published by Arthur Kunz.


Clinical Cancer Research | 2004

Potent and Specific Antitumor Efficacy of CMC-544, a CD22-Targeted Immunoconjugate of Calicheamicin, against Systemically Disseminated B-Cell Lymphoma

John F. DiJoseph; Mary E. Goad; Maureen Dougher; Erwin R. Boghaert; Arthur Kunz; Philip Ross Hamann; Nitin K. Damle

Purpose: CMC-544 is a CD22-targeted immunoconjugate of calicheamicin and exerts a potent cytotoxic effect against CD22+ B-cell lymphoma. This study evaluated antitumor efficacy of CMC-544 against systemically disseminated B-cell lymphoma. Experimental Design: Scid mice received i.v. injections of CD22+ Ramos B-cell lymphoma cells for their systemic dissemination. CMC-544, G5/44, CD33-targeted CMA-676 (control conjugate) or rituximab were given i.p. 3, 9, 15, or 21 days after B-cell lymphoma dissemination. Diseased mice were monitored daily for hind-limb paralysis and death. Histopathological examination of CMC-544-treated and vehicle-treated diseased mice was also performed. Results: Mice with disseminated B-cell lymphoma developed hind-limb paralysis within 35 days. When given up to 15 days after B-cell lymphoma dissemination, CMC-544 extended survival of the diseased mice to >100 days, and these mice were considered cured. CMC-544 was efficacious when given during both the early initiation phase and the late established phase of the disease. A single dose of CMC-544 was effective in delaying the occurrence of hind-limb paralysis. In contrast, neither CMA-676 nor unconjugated G5/44 was effective. Rituximab was effective when given early in the disease process but not when the disease was established. Histopathological analysis revealed B-cell lymphoma infiltration in brain, spinal cord, bone marrow, and kidney in vehicle-treated but not in CMC-544–treated diseased mice. Consistent with its efficacy against the disseminated B-cell lymphoma, CMC-544 also caused regression of established Ramos B-cell lymphoma xenografts in scid mice. Conclusions: CMC-544 confers strong therapeutic activity against systemic disseminated B-cell lymphoma and protects mice from hind-limb paralysis and death. These results support clinical evaluation of CMC-544 in the treatment of CD22+ lymphoid malignancies.


Clinical Cancer Research | 2004

Antibody-Targeted Chemotherapy with the Calicheamicin Conjugate hu3S193-N-Acetyl γ Calicheamicin Dimethyl Hydrazide Targets Lewisy and Eliminates Lewisy-Positive Human Carcinoma Cells and Xenografts

Erwin R. Boghaert; Latha Sridharan; Douglas Armellino; Kiran Khandke; John F. DiJoseph; Arthur Kunz; Maureen Dougher; Fan Jiang; Lyka B. Kalyandrug; Philip Ross Hamann; Philip Frost; Nitin K. Damle

Purpose: Linking a cytotoxic anticancer drug to an antibody that recognizes a tumor-associated antigen can improve the therapeutic index of the drug. We asked whether a conjugate of the cytotoxic antibiotic N-acetyl γ calicheamicin dimethyl hydrazide (CalichDMH) and an antibody recognizing Lewisy (Ley) antigen could eliminate carcinomas that express Ley. Because Ley is highly expressed on carcinomas of colon, breast, lung, ovary, and prostate, a CalichDMH conjugate targeting Ley could provide a treatment option for various cancers. Experimental Design: The humanized anti-Ley antibody hu3S193 was conjugated to CalichDMH via the bifunctional AcBut linker. Selectivity and avidity of the conjugate (hu3S193-CalichDMH) for Ley-BSA or Ley+ cells was tested by BIAcore or flow cytometry. Cytotoxicity of hu3S193-CalichDMH was compared with toxicity of a control conjugate on monolayers of Ley+ and Ley− carcinoma cells. Inhibition of tumor growth by hu3S193-CalichDMH was assessed on three types of s.c. xenografts. Results: Hu3S193-CalichDMH had similar selectivity as hu3S193. The conjugate had lower affinity for Ley-BSA but not for Ley+ cells. When tested on monolayers of human Ley+ carcinoma cells, hu3S193-CalichDMH was more cytotoxic than a control conjugate. This difference in efficacy was not noted on Ley− cells. Efficacy of hu3S193-CalichDMH depended on the expression of Ley and on the sensitivity of the cells to CalichDMH. In vivo, hu3S193-CalichDMH inhibited growth of xenografted human gastric (N87), colon (LOVO), and prostate carcinomas (LNCaP). When used against N87 xenografts, hu3S193-CalichDMH arrested tumor growth for at least 100 days. Conclusion: Hu3S193-CalichDMH can specifically eliminate Ley+ tumors. These results support development of this conjugate for treatment of carcinomas.


Cancer Immunology, Immunotherapy | 2005

Antibody-targeted chemotherapy of B-cell lymphoma using calicheamicin conjugated to murine or humanized antibody against CD22

John F. DiJoseph; Andrew George Popplewell; Simon Peter Tickle; Heather Margaret Ladyman; Alastair David Griffiths Lawson; Arthur Kunz; Kiran Khandke; Douglas Armellino; Erwin R. Boghaert; Philip Ross Hamann; Karen Zinkewich-Peotti; Sue Stephens; Neil Weir; Nitin K. Damle

Antibody-targeted chemotherapy with immunoconjugates of calicheamicin is a clinically validated strategy in cancer therapy. This study describes the selection of a murine anti-CD22 mAb, m5/44, as a targeting agent, its conjugation to a derivative of calicheamicin (CalichDM) via either acid-labile or acid-stable linkers, the antitumor activity of CalichDM conjugated to m5/44, and its subsequent humanization by CDR grafting. Murine IgG1 mAb m5/44 was selected based on its subnanomolar affinity for CD22 and ability to be internalized into B cells. CalichDM conjugated to m5/44 caused potent growth inhibition of CD22+ human B-cell lymphomas (BCLs) in vitro. The conjugate of m5/44 with an acid-labile linker was more potent than an acid-stable conjugate, a nonbinding conjugate with a similar acid-labile linker, or unconjugated CalichDMH in inhibiting BCL growth. CalichDM conjugated to m5/44 caused regression of established BCL xenografts in nude mice. In contrast, both unconjugated m5/44 and a nonbinding conjugate were ineffective against these xenografts. Based on the potent antitumor activity of m5/44-CalichDM conjugates, m5/44 was humanized by CDR grafting to create g5/44, an IgG4 anti-CD22 antibody. Both m5/44 and g5/44 bound CD22 with subnanomolar affinity. Competitive blocking with previously characterized murine anti-CD22 mAbs suggested that g5/44 recognizes epitope A located within the first N-terminal Ig-like domain of human CD22. Antitumor efficacy of CalichDM conjugated to g5/44 against BCL xenografts was more potent than its murine counterpart. Based on these results, a calicheamicin conjugate of g5/44, CMC-544, was selected for further development as a targeted chemotherapeutic agent for the treatment of B-cell malignancies.


Cancer Research | 2011

Delineation of a Cellular Hierarchy in Lung Cancer Reveals an Oncofetal Antigen Expressed on Tumor-Initiating Cells

Marc Damelin; Kenneth G. Geles; Ping Yuan; Michelle Baxter; Jonathon Golas; John F. DiJoseph; Maha Karnoub; Shuguang Huang; Veronica Diesl; Carmen Behrens; Sung E. Choe; Carol Rios; Latha Sridharan; Maureen Dougher; Arthur Kunz; Philip Ross Hamann; Deborah Evans; Douglas Armellino; Kiran Khandke; Kimberly Marquette; Lioudmila Tchistiakova; Erwin R. Boghaert; Robert T. Abraham; Ignacio I. Wistuba; Bin-Bing S. Zhou

Poorly differentiated tumors in non-small cell lung cancer (NSCLC) have been associated with shorter patient survival and shorter time to recurrence following treatment. Here, we integrate multiple experimental models with clinicopathologic analysis of patient tumors to delineate a cellular hierarchy in NSCLC. We show that the oncofetal protein 5T4 is expressed on tumor-initiating cells and associated with worse clinical outcome in NSCLC. Coexpression of 5T4 and factors involved in the epithelial-to-mesenchymal transition were observed in undifferentiated but not in differentiated tumor cells. Despite heterogeneous expression of 5T4 in NSCLC patient-derived xenografts, treatment with an anti-5T4 antibody-drug conjugate resulted in complete and sustained tumor regression. Thus, the aggressive growth of heterogeneous solid tumors can be blocked by therapeutic agents that target a subpopulation of cells near the top of the cellular hierarchy.


Cancer Immunology, Immunotherapy | 2007

CD20-specific antibody-targeted chemotherapy of non-Hodgkin’s B-cell lymphoma using calicheamicin-conjugated rituximab

John F. DiJoseph; Maureen Dougher; Douglas Armellino; Lyka B. Kalyandrug; Arthur Kunz; Erwin R. Boghaert; Philip Ross Hamann; Nitin K. Damle

Tumor-targeted delivery of a potent cytotoxic agent, calicheamicin, using its immunoconjugates is a clinically validated therapeutic strategy. Rituximab is a human CD20-specific chimeric antibody extensively used in B-NHL therapy. We investigated whether conjugation to calicheamicin can improve the anti-tumor activity of rituximab against human B-cell lymphoma (BCL) xenografts in preclinical models. BCL cells were cultured with rituximab or its calicheamicin conjugates and their in vitro growth was monitored. BCL cells were injected s.c. to establish localized xenografts in nude mice or i.v. to establish disseminated BCL in severe combined immunodeficient (scid) mice. I.p. treatment with rituximab or its calicheamicin conjugates was initiated and its effect on s.c. BCL growth or survival of mice with disseminated BCL was monitored. Conjugation of calicheamicin to rituximab vastly enhanced its growth inhibitory activity against BCL in vitro. Conjugation to calicheamicin had no deleterious effect on the effector functional activity of rituximab. Calicheamicin conjugated to rituximab with an acid-labile linker exhibited greater anti-tumor activity against s.c. BCL xenografts and improved survival of mice with disseminated BCL over that of unconjugated rituximab. Anti-tumor activities of rituximab conjugated to calicheamicin via an acid-stable linker were similar to that of unconjugated rituximab. Superior anti-tumor efficacy exhibited by a calicheamicin immunoconjugate of rituximab with an acid-labile linker over that of rituximab demonstrates the therapeutic potential of CD20-specific antibody-targeted chemotherapy strategy in the treatment of B-NHL.


Molecular Immunology | 1992

Microheterogeneity of a purified IgG1, due to asymmetric fab glycosylation

Ruth Grebenau; David M. Goldenberg; Chang Chien-Hsing; George A. Koch; David V. Gold; Arthur Kunz; Hans J. Hansen

A murine monoclonal anti-granulocyte IgG1, IMMU-MN3, was seen to exhibit heterogeneity. On reduced SDS-PAGE, the purified antibody appeared as two heavy-chain bands of unequal intensity, and only one light-chain band. Hydrophobic interaction chromatography (HIC) also resolved two populations of the IMMU-MN3 antibody. Based on Concanavalin A affinity chromatography, enzymatic digestion with Endoglycosidase F and carbohydrate analysis, it was found that the heterogeneity detected by SDS-PAGE and HIC was due to differences in glycosylation. Furthermore, sequential gel analysis (non-reduced/reduced) demonstrated that the upper heavy-chain band was asymmetrically glycosylated.


Cancer treatment and research | 1990

Labeling of anti-tumor antibodies and antibody fragments with Tc-99m

Hans J. Hansen; Anastasia L. Jones; Ruth Grebenau; Arthur Kunz; David M. Goldenberg

The utility of radiolabeled monoclonal antibodies (Mabs) and Mab fragments in the radioimmunodetection (RAID) of cancer has been established with 131I, 111In, and 123I [1–9]. More recently, however, increasing efforts have been expended to label these reagents with 99mTc. Indeed, successful clinical application of commercial monoclonal antibody imaging products will probably be dependent on the development of simple, inexpensive methods to label antibody or antibody fragments with this radionuclide. When compared with other radionuclides used to label Mabs, 99mTc has the following advantages: low cost, ready availability, ideal nuclear properties for gamma cameras, and reduced patient radiation exposure per millicurie of radionuclide administered. Strategies employed by different investigators to label antibodies and antibody fragments with 99mTc fall into two major categories. In one approach, efforts have been made to use a ligand to attach 99mTc indirectly to the antibody. The second approach has been to bind the radionuclide directly to intrinsic receptor sites or to altered groups of the protein backbone of the antibody molecule.


Cancer Research | 2011

Abstract 475: Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells

Marc Damelin; Kenneth G. Geles; Ping Yuan; Michelle Baxter; Jonathon Golas; Shuguang Huang; John F. DiJoseph; Veronica Diesl; Carmen Behrens; Sung E. Choe; Carol Rios; Latha Sridharan; Maureen Dougher; Arthur Kunz; Philip Ross Hamann; Deborah Evans; Douglas Armellino; Kiran Khandke; Kimberly Marquette; Lioudmila Tchistiakova; Erwin R. Boghaert; Robert T. Abraham; Ignacio I. Wistuba; Bin-Bing S. Zhou

Poorly differentiated tumors in non-small cell lung cancer (NSCLC) are refractory to chemotherapy and associated with short survival time. Here we integrate multiple experimental models with clinicopathological analysis of patient tumors to delineate a cellular hierarchy in NSCLC. We demonstrate that the oncofetal protein 5T4 is expressed on tumor-initiating cells and associated with worse clinical outcome in NSCLC. Coexpression of 5T4 and factors involved in the epithelial-to-mesenchymal transition was observed in undifferentiated but not in differentiated tumor cells. Despite heterogeneous expression of 5T4 in NSCLC patient-derived xenografts, treatment with an anti-5T4 antibody-drug conjugate resulted in complete and sustained tumor regression. Thus, the aggressive growth of heterogeneous solid tumors can be blocked by therapeutic agents that target a subpopulation of cells near the top of the cellular hierarchy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 475. doi:10.1158/1538-7445.AM2011-475


Blood | 2004

Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies

John F. DiJoseph; Douglas Armellino; Erwin R. Boghaert; Kiran Khandke; Maureen Dougher; Latha Sridharan; Arthur Kunz; Philip Ross Hamann; Boris Gorovits; Chandrasekhar Udata; Justin K. Moran; Andrew G. Popplewell; Sue Stephens; Philip Frost; Nitin K. Damle


Archive | 2003

Calicheamicin derivative-carrier conjugates

Arthur Kunz; Justin Keith Moran; Joseph Thomas Rubino; Neera Jain; Eugene Vidunas; John Simpson; Paul David Robbins; Nishith Merchant; John F. DiJoseph; Mark Edward Ruppen; Nitin K. Damle; Andrew George Popplewell

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