This Article Full Text (PDF) References Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Bugelskil, P J Articles by Hart, T K Search for Related Content PubMed PubMed Citation Articles by Bugelskil, P J Articles by Hart, T K Pubmed/NCBI databases Substance via MeSH Social Bookmarking                   What's this?

Preclinical development of keliximab, a Primatized^TM anti-CD4 monoclonal antibody, in human CD4 transgenic mice: characterization of the model and safety studies

D J Herzykl

S Rehm

Department of Safety Assessment, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA

A G Harmsen

Trudeau Institute, Saranac Lake, New York 12938, USA

E V Gore

D M Williams

B E Maleeff

Department of Safety Assessment, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA

A M Badger

Department of Bone Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA

A Truneh

Department of Immunology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA

S R O'Brien

R A Macial

P J Wier

D G Morgan

Department of Safety Assessment, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA

T K Hart

Department of Safety Assessment, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA; Safety Assessment, Mail StopUE0462, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA

The preclinical safety assessment of biopharmaceuticals necessitates that studies be conducted in species in which the products are pharmacologically active. Monoclonal anti-bodies are a promising class ofbiopharmaceuticals for many disease indications; however, by design, these agents tend to have limited species cross-reactivity and tend to only be active in primates. Keliximab is a human-cynomolgus monkey chimeric (Primatized&) monoclonal antibody with specificity for human and chimpanzee CD4. In order to conduct a comprehensive preclinical safety assessment of this antibody to support chronic treatment of rheumatoid arthritis in patients, a human CD4 transgenic mouse was used for chronic and reproductive toxicity studies and for genotoxic studies. In addition, immunotoxicity studies were conducted in these mice with Candida albicans, Pneumo- cystis carinii and B16 melanoma cells to assess the effects of keliximab on host resistance to infection and immunosur-veillance to neoplasia. The results of these studies found keliximab to be well tolerated with the only effects observed being related to its pharmacologic activity on CD4 + T lymphocytes. The use of transgenic mice expressing human proteins provides a useful alternative to studies in chimpan-zees with biopharmaceutical agents having limited species cross-reactivity.

Key Words: anti-CD4monoclonalantibody • transgenicmice • biopharmaceutical • preclinicalsafetyassessment • hostdefense

Human & Experimental Toxicology, Vol. 19, No. 4, 230-243 (2000)
DOI: 10.1191/096032700678815783


CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. L. Bussiere, P. Martin, M. Horner, J. Couch, M. Flaherty, L. Andrews, J. Beyer, and C. Horvath Alternative Strategies for Toxicity Testing of Species-Specific Biopharmaceuticals International Journal of Toxicology, May 1, 2009; 28(3): 230 - 253. [Abstract] [Full Text] [PDF]

				T. Pelat, M. Hust, E. Laffly, F. Condemine, C. Bottex, D. Vidal, M.-P. Lefranc, S. Dubel, and P. Thullier High-Affinity, Human Antibody-Like Antibody Fragment (Single-Chain Variable Fragment) Neutralizing the Lethal Factor (LF) of Bacillus anthracis by Inhibiting Protective Antigen-LF Complex Formation Antimicrob. Agents Chemother., August 1, 2007; 51(8): 2758 - 2764. [Abstract] [Full Text] [PDF]

				E. Laffly, L. Danjou, F. Condemine, D. Vidal, E. Drouet, M.-P. Lefranc, C. Bottex, and P. Thullier Selection of a Macaque Fab with Framework Regions Like Those in Humans, High Affinity, and Ability To Neutralize the Protective Antigen (PA) of Bacillus anthracis by Binding to the Segment of PA between Residues 686 and 694 Antimicrob. Agents Chemother., August 1, 2005; 49(8): 3414 - 3420. [Abstract] [Full Text] [PDF]

				D J Herzyk, P J Bugelski, T K Hart, and P J Wier Practical aspects of including functional endpoints in developmental toxicity studies. Case study: immune function in HuCD4 transgenic mice exposed to anti-CD4 MAb in utero Human and Experimental Toxicology, September 1, 2002; 21(9-10): 507 - 512. [Abstract] [PDF]