Preclinical development of keliximab,a Primatized™ anti-CD4 monoclonal antibody,in human CD4 transgenic mice: characterization of the model and safety studies
Free accessResearch articleFirst published online April, 2000
Preclinical development of keliximab,a Primatized™ anti-CD4 monoclonal antibody,in human CD4 transgenic mice: characterization of the model and safety studies
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.
1 Ellmeier W , Sawada S , Littman DR.The regulation of CD4 and CD8 coreceptor gene expression during T cell developmentAnnual Review of Immunology1999; 17: 523-554 .
2.
2 Veillette A , Bookman MA , Horak EM , Bolen JB.The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p561ck . Cell1988; 55 (2): 301-308 .
3.
3 Breedveld FC.Monoclonal antibodies to CD4 . Rheumatic Diseases Clinics of North America1998; 24 (3): 567-578 .
4.
4 Choy EH , Kingsley GH , Panayi GS.Anti-CD4 mono-clonal antibodies in rheumatoid arthritis . Springer Seminars in Immunopathology1998; 20 (1-2): 261-273 .
5.
5 Kon OM , Kay AB.T cells and chronic asthma . Interna-tionalArchives of Allergy and Immunology1999; 118 (2): 133-135 .
6.
6 Anderson D , Chambers K , Hanna N , Leonard J , Reff M , Newman R , Baldoni J , Dunleavy D , Reddy M , Sweet R , Truneh A.A primatized3 MAb to human CD4 causes receptor modulation, without marked reduction in CD4+ T cells in chimpanzees: in vitro and in vivo: characterization of a MAb (IDEC-CE9.1) to human CD4 . Clinical Immunology and Immunopathology1997; 84 (1): 73-84 .
7.
7 Davis CB , Garver EM , Kwok DC , Urbanski JJ.Disposition of metabolically radiolabeled CE9.1-a macaque-human chimeric anti-human CD4 monoclo-nal antibody-in transgenic mice bearing human CD4 . Drug Metabolism and Disposition1996; 24 (9): 1032-1037 .
8.
8 Kon OM , Sihra BS , Compton CH , Leonard TB , Kay AB , Barnes NC.Randomised, dose-ranging, placebo-con-trolled study of chimeric antibody to CD4 (keliximab) in chronic severe asthma . Lancet1998; 352 (4): 1109-1113 .
9.
9 Yocum DE , Solinger AM , Tesser J , Gluck O , Cornett M , O'Sullivan F , Nordensson K , Dallaire B , Shen CD , Lipani J.Clinical and immunologic effects of a Preclinical development in CD4 transgenic mice PJ Bugelski et al 242 PRIMATIZED' anti-CD4 monoclonal antibody in active rheumatoid arthritis: results of a phase I, single dose escalating trial . Journal of Rheumatology1998; 25 (7): 1257-1262 .
10.
10 Killeen N , Sawada S , Littman DR.Regulated expression of human CD4 rescues helper T cell development in mice lacking expression of endogenous CD4 . EMBO Journal1993; 12 (4): 1547-1553 .
11.
11 Guide for the Care and Use of Laboratory Animals, NIH Publication No. 86-23, U.S. Department of Health and Human Services , 1996.
12.
12 Gossett KA , Narayanan PK , Williams DM , Gore ER , Herzyk DJ , Hart TK , Sellers TS.Flow cytometry in the preclinical development of biopharmaceuticals . Toxico-logic Pathology1999; 27 (1): 32-37 .
13.
13 Badger AM , Newman-Tarr TM , Satterfield JL.Selective immunomodulatory activity of SK&F 106615, a macro-phage-targeting antiarthritic compound, on antibody and cellular responses in rats and mice . Immunophar-macology1997; 37 (1): 53-61 .
14.
14 Badger AM , DiMartino MJ , Swift BA , Mirabelli CK.Immunomodulatory activity and non-specific suppres-sor cell generation by spirogermanium in murine and rat models of cell-mediated immunity . Immunophar-macology1988; 16: 33-43 .
15.
15 Griswold DE , Webb EF , Badger AM , Gorycki PD , Levandoski PA , Barnette MA , Grous M , Christensen S , Torphy TJ. SB 207499 (Ariflo), a second generation phosphodiesterase 4 inhibitor, reduces tumor necrosis factor alpha and interleukin-4 production in vivo . Journal of Pharmacology and Experimental Therapeutics1998; 287 (2): 705-711 .
16.
16 Elvin P , Evans CW.Cell adhesion and experimental metastasis: a study using the B16 malignant melanoma model system . European Journal of Cancer and Clinical Oncology1984; 20 (1): 107-114 .
17.
17 Murray MJ , Lauer LD , Luster MI , Luebke RW , Adams DO , Dean JH.Correlation of murine susceptibility to tumor, parasite and bacterial challenge with altered cell-mediated immunity following systemic exposure to the tumor promoter phorbol myristate acetate . Interna-tional Journal of Immunopharmacology1985; 7 (4): 491-500 .
18.
18 Herzyk DJ , Ruggieri EV , Cunningham L , Polsky R , Herold C , Klinkner AM , Badger A , Kerns WD , Bugelski PJ.Single-organism model of host defense against infection: a novel immunotoxicologic approach to evaluate immunomodulatory drugs . Toxicologic Pathology1997; 25: 351-362 .
19.
19 Harmsen AG , Stankiewicz M.Requirement for CD4 + cells in resistance to Pneumocystis carinii pneumonia in mice . Journal of Experimental Medicine1990; 172 (3): 937-945 .
20.
20 International Committee on Harmonization . ICH Topic S6. Preclinical evaluation of biotechnology-derived pharmaceuticals. July 1996.
21.
21 Kirkland DJ.Use of transgenic animals in toxicology . Pharmaceutical Sciences and Technology Today1998; 1: 62-68 .
22.
22 Lovik M.Mutant and transgenic mice in immunotoxicol-ogy: an introduction . Toxicology1997; 119 (1): 65-76 .
23.
23 Liggitt HD , Reddington GM.Transgenic animals in the evaluation of compound efficacy and toxicity: will they be as useful as they are novel?Xenobiotica1992; 22 (9-10): 1043-1054 .
24.
24 Cordaro JC.Transgenic mice as future tools in risk assessment . RiskAnalysis1989; 9 (2): 157-168 .
25.
25 Eastin WC.The U.S. National Toxicology Program evaluation of transgenic mice as predictive models for identifying carcinogens . Environmental Health Perspec-tives 106 Suppl1998; 106(Suppl 1): 81-84 .
26.
26 Cammarota G , Scheirle A , Takacs B , Doran DM , Knorr R , Bannwarth W , Guardiola J , Sinigaglia F.Identification of a CD4 binding site on the beta 2 domain of HLA-DR molecules . Nature1992; 356 (2): 799-801 .
27.
27 Clayton LK , Sieh M , Pious DA , Reinherz EL.Identifica-tion of human CD4 residues affecting class II MHC versus HIV-1 gpl20 binding . Nature1989; 339 (5): 548-551 .
28.
28 Doyle C , Strominger JL.Interaction between CD4 and class II MHC molecules mediates cell adhesion . Nature1987; 330 (5): 256-259 .
29.
29 Glaichenhaus N , Shastri N , Littman DR , Turner JM.Requirement for association of p561ck in antigen-specific signal transduction in T cells . Cell1991; 64 (3): 511-520 .
30.
30 von Hoegen P , Miceli MC , Tourvieille B , Schilhamn M , Parnes JR.Equivalence of human and mouse CD4 in enhancing antigen responses by a mouse class II restricted T cell hybridoma . Journal of Experimental Medicine1989; 170 (6): 1879-1886 .
31.
31 International Committee on Harmonization . ICH Topic SlA. The need for carcinogenicity studies of pharma-ceuticals. March 1996.
32.
32 Jung KC , Park WS , Lee YJ , Chung DH , Choi EY , Kim SH , Bae JM , Sung U , Bae YM , Park SH.Development of a new anti-CD4 monoclonal antibody (YG23) which inhibits the formation of colonies of human bone marrow progenitor cells . Molecules and Cells1998; 8 (2): 169-174 .
33.
33 Jin FS , Youle RJ , Johnson VG , Shiloach J , Fass R , Longo DL , Bridges SH.Suppression of the immune response to immunotoxins with anti-CD4 monoclonal antibodies . Journal of Immunology1991; 146 (6): 1806-1811 .
34.
34 Ma D , Niederkorn JY.Efficacy of tumor-infiltrating lymphocytes in the treatment of hepatic metastases arising from transgenic intraocular tumors in mice . Investigative Ophthalmology and Visual Science1995; 36 (6): 1067-1075 .
35.
35 Lode HN , Xiang R , Becker JC , Gillies SD , Reisfeld RA.Immunocytokines: a promising approach to cancer immunotherapy . Pharmacology and Therapeutics1998; 80 (3): 277-292 .
36.
36 Rakhmilevich AL , North RJ.Elimination of CD4 + T cells in mice bearing an advanced sarcoma augments the antitumor action of interleukin-2 . Cancer Immunology and Immunotherapy1994; 38 (2): 107-112 .
37.
37 Schild HJ , Kyewski B , von Hoegen P , Schirrmacher V.CD4+ helper T cells are required for resistance to a highly metastatic murine tumor . European Journal of Immunology1987; 17 (2): 1863-1866 .
38.
38 Markovic SN , Murasko DM.Role of natural killer and T-cells in interferon induced inhibition of spontaneous metastasis of B16F1OL murine melanoma . Cancer Research1991; 51 (4): 1124-1128 .
39.
39 Weber SM , Shi F , Heise C , Warner T , Mahvi DM.Interleukin-12 gene transfer results in CD8-dependent regression of murine CT26 liver tumors . Annals of Surgical Oncology1999; 6 (2): 186-194 .
40.
40 Gill HS , Watson DL , Brandon MR.In vivo inhibition by a monoclonal antibody to CD4 + T cells of humoral and cellular immunity in sheep . Immunology1992; 77 (1): 38-42 .
41.
41 Carteron NL , Wofsy D , Seaman WE.Induction of immune tolerance during administration of monoclonal antibody to L3T4 does not depend on depletion of L3T4 + cells . Journal of Immunology1988; 140 (3): 713-716 .
42.
42 Elliott BE , Ekblom P , Pross H , Niemann A , Rubin K.Anti-beta 1 integrin IgG inhibits pulmonary macrome-tastasis and the size of micrometastases from a murine mammnary carcinoma . Cell Adhesion and Communica-tion1994; 1 (4): 319-332 .
43.
43 Hirsch R , Chatenoud L , Gress RE , Bach JF , Sachs DH , Bluestone JA.Suppression of the humoral response to anti-CD3 mAB by pretreatment with anti-CD4 mAB . Transplantation Proceedings1989; 21 (1): 1015-1016 .
44.
44 Weyand CM , Goronzy J , Swarztrauber K , Fathman CG.Immunosuppression by anti-CD4 treatment in vivo. Cellular and humoral responses to alloantigens . Trans-plantation1989; 47 (6): 1039-1042 .
45.
45 Zuniga-Pflucker JC , McCarthy SA , Weston M , Longo DL , Singer A , Kruisbeek AM.Role of CD4 in thymocyte selection and maturation . Journal of Experimental Medicine1989; 169 (6): 2085-2096 .
46.
46 Fleming AL , Field EH , Tolaymat N , Cowdery JS.Age influences recovery of systemic and mucosal immune responses following acute depletion of CD4 T cells . Clinical Immunology and Immunopharmacology1993; 69(3): 285-291 .
47.
47 Silva EM , Bertho AL , Mendonca SC.Effect of in vivo depletion of CD4 + T cells on experimental infection of susceptible BALB/c mice with Leishmania amazonen-. sis .Acta Tropica1994; 56 (1): 111-120 .
48.
48 Fidel PL Jr , Lynch ME , Sobel JD.Circulating CD4 and CD8 T cells have little impact on host defense against experimental vaginal candidiasis . Infection and Immu-nity1995; 63 (7): 2403-2408 .
49.
49 Harmsen AG , Chen W , Gigliotti F.Active immunity to Pneumocystis carinii reinfection in T-cell-de-pleted mice . Infection and Immunity1995; 63 (7): 2391-2395 .
50.
50 Shellito J , Suzara VV , Blumenfeld W , Beck JM , Steger HJ , Ermak TH.A new model of Pneumocystis carinii infection in mice selectively depleted of helper T lymphocytes . Journal of Clinical Investigation1990; 85 (5): 1686-1693 .
