Galiximab (anti-CD80)-induced growth inhibition and prolongation of survival in vivo of B-NHL tumor xenografts and potentiation by the combination with fludarabine

Hariharan,Kandasamy; Chu,Peter; Murphy,Tracey; Clanton,Dana; Berquist,Lisa; Molina,Arturo; Ho,Steffan  N.; Vega,Mario  I.; Bonavida,Benjamin

doi:10.3892/ijo.2013.1986

August 2013 Volume 43 Issue 2

Full Size Image

Cover Legend PDF

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

August 2013 Volume 43 Issue 2

Full Size Image

Cover Legend PDF

Article

Galiximab (anti-CD80)-induced growth inhibition and prolongation of survival in vivo of B-NHL tumor xenografts and potentiation by the combination with fludarabine

Authors:
- Kandasamy Hariharan
- Peter Chu
- Tracey Murphy
- Dana Clanton
- Lisa Berquist
- Arturo Molina
- Steffan N. Ho
- Mario I. Vega
- Benjamin Bonavida
View Affiliations / Copyright

Affiliations: Cancer Therapeutics, Biogen Idec, San Diego, CA 92122, USA, Hematology/Oncology, Biogen Idec, San Diego, CA 92122, USA, Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA
Pages: 670-676
|
Published online on: June 13, 2013

https://doi.org/10.3892/ijo.2013.1986
Expand metrics +

Abstract

Galiximab is a primatized monoclonal antibody that targets CD80 expressed on malignant B cells and is being studied in the clinic as a potential treatment for follicular NHL. We have recently reported that galiximab signals B-NHL cells in vitro and inhibits cell growth and sensitizes resistant tumor cells to apoptosis by chemotherapeutic drugs. This study was designed to validate the in vitro findings in in vivo in mice. Thus, we examined in vivo the antitumor activity of galiximab used alone and in combination with chemotherapeutic agents in SCID mice bearing human lymphoma xenografts. The in vivo antitumor effects of galiximab used alone and in combination with fludarabine or doxorubicin were determined in solid and disseminated human B-lymphoma tumors grown in SCID mice. Galiximab monotherapy in vivo demonstrated significant antitumor activity in a Raji lymphoma solid tumor model and in an SKW disseminated lymphoma tumor model. There was significant inhibition in tumor growth and prolongation of survival. In vitro, galiximab sensitized Raji cells to apoptosis by both fludarabine and doxorubicin. Tumor growth inhibition was significantly enhanced when the mice were treated with the combination of galiximab and fludarabine. These findings support the potential clinical application of galiximab in combination with chemotherapeutic drugs for the treatment of CD80-expressing hematological malignancies.

View Figures

View References

1.	Armitage JO: Treatment of non-Hodgkin’s lymphoma. N Engl J Med. 328:1023–1030. 1993.
2.	Sawas A, Diefenbach C and O’Connor OA: New therapeutic targets and drugs in non-Hodgkin’s lymphoma. Curr Opin Hematol. 18:280–287. 2011.
3.	Ferrario A, Pulsoni A, Olivero B, et al: Fludarabine, cyclophosphamide, and rituximab in patients with advanced, untreated, indolent B-cell nonfollicular lymphomas: phase 2 study of the Italian Lymphoma Foundation. Cancer. 118:3954–3961. 2012. View Article : Google Scholar : PubMed/NCBI
4.	Montoto S and Fitzgibbon J: Transformation of indolent B-cell lymphomas. J Clin Oncol. 29:1827–1834. 2011. View Article : Google Scholar
5.	Molina A: A decade of rituximab: improving survival outcomes in non-Hodgkin’s lymphoma. Annu Rev Med. 59:237–250. 2008.PubMed/NCBI
6.	Coyle AJ and Gutierrez-Ramos JC: The expanding B7 superfamily: increasing complexity in costimulatory signals regulating T cell function. Nat Immunol. 2:203–209. 2001. View Article : Google Scholar : PubMed/NCBI
7.	Lanier LL, O’Fallon S, Somoza C, et al: CD80 (B7) and CD86 (B70) provide similar costimulatory signals for T cell proliferation, cytokine production, and generation of CTL. J Immunol. 154:97–105. 1995.PubMed/NCBI
8.	Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 12:252–264. 2012. View Article : Google Scholar : PubMed/NCBI
9.	Dorfman DM, Schultze JL, Shahsafaei A, et al: In vivo expression of B7-1 and B7-2 by follicular lymphoma cells can prevent induction of T-cell anergy but is insufficient to induce significant T-cell proliferation. Blood. 90:4297–4306. 1997.PubMed/NCBI
10.	Munro JM, Freedman AS, Aster JC, et al: In vivo expression of the B7 costimulatory molecule by subsets of antigen-presenting cells and the malignant cells of Hodgkin’s disease. Blood. 83:793–798. 1994.PubMed/NCBI
11.	Vyth-Dreese FA, Dellemijn TA, Majoor D and de Jong D: Localization in situ of the co-stimulatory molecules B7.1, B7.2, CD40 and their ligands in normal human lymphoid tissue. Eur J Immunol. 25:3023–3029. 1995. View Article : Google Scholar : PubMed/NCBI
12.	Delabie J, Ceuppens JL, Vandenberghe P, de Boer M, Coorevits L and De Wolf-Peeters C: The B7/BB1 antigen is expressed by Reed-Sternberg cells of Hodgkin’s disease and contributes to the stimulating capacity of Hodgkin’s disease-derived cell lines. Blood. 82:2845–2852. 1993.PubMed/NCBI
13.	Suvas S, Singh V, Sahdev S, Vohra H and Agrewala JN: Distinct role of CD80 and CD86 in the regulation of the activation of B cell and B cell lymphoma. J Biol Chem. 277:7766–7775. 2002. View Article : Google Scholar : PubMed/NCBI
14.	Czuczman MS, Thall A, Witzig TE, et al: Phase I/II study of galiximab, an anti-CD80 antibody, for relapsed or refractory follicular lymphoma. J Clin Oncol. 23:4390–4398. 2005. View Article : Google Scholar : PubMed/NCBI
15.	Leonard JP, Friedberg JW, Younes A, et al: A phase I/II study of galiximab (an anti-CD80 monoclonal antibody) in combination with rituximab for relapsed or refractory, follicular lymphoma. Ann Oncol. 18:1216–1223. 2007. View Article : Google Scholar : PubMed/NCBI
16.	Czuczman MS, Leonard JP, Jung S, et al: Phase II trial of galiximab (anti-CD80 monoclonal antibody) plus rituximab (CALGB 50402): Follicular Lymphoma International Prognostic Index (FLIPI) score is predictive of upfront immunotherapy responsiveness. Ann Oncol. 23:2356–2362. 2012. View Article : Google Scholar
17.	Martinez-Paniagua MA, Vega MI, Huerta-Yepez S, et al: Galiximab signals B-NHL cells and inhibits the activities of NF-kappaB-induced YY1- and snail-resistant factors: mechanism of sensitization to apoptosis by chemoimmuno-therapeutic drugs. Mol Cancer Ther. 11:572–581. 2012. View Article : Google Scholar
18.	Younes A, Hariharan K, Allen RS and Leigh BR: Initial trials of anti-CD80 monoclonal antibody (Galiximab) therapy for patients with relapsed or refractory follicular lymphoma. Clin Lymphoma. 3:257–259. 2003. View Article : Google Scholar : PubMed/NCBI
19.	Vega MI, Huerta-Yepez S, Jazirehi AR, Garban H and Bonavida B: Rituximab (chimeric anti-CD20) sensitizes B-NHL cell lines to Fas-induced apoptosis. Oncogene. 24:8114–8127. 2005.PubMed/NCBI
20.	Jazirehi AR and Bonavida B: Cellular and molecular signal transduction pathways modulated by rituximab (rituxan, anti-CD20 mAb) in non-Hodgkin’s lymphoma: implications in chemosensitization and therapeutic intervention. Oncogene. 24:2121–2143. 2005.PubMed/NCBI
21.	Vega MI, Baritaki S, Huerta-Yepez S, Martinez-Paniagua MA and Bonavida B: A potential mechanism of rituximab-induced inhibition of tumor growth through its sensitization to tumor necrosis factor-related apoptosis-inducing ligand-expressing host cytotoxic cells. Leuk Lymphoma. 52:108–121. 2011. View Article : Google Scholar