Monoclonal primatized

In chimpanzees, administration of Fab fragments of a monoclonal anti-F-VII antibody preceding an endotoxin bolus injection effectively blocked the activation of the coagulation pathway (B25). Administration of monoclonal anti-lL-6 under the same experimental conditions attenuated the activation of coagulation, while the fibrinolytic system remained unaltered. However, administration of monoclonal anti-TNF enhanced the tendency to microvascular thrombosis (P17,18). Monoclonal anti-TF antibodies administered to baboons as a pretreatment attenuated coagulopathy after induction of E. coli sepsis in these animals (T4). Primates pretreated with anti-C5a antibodies before infusion of E. coli developed less hypotension and had better survival rates than untreated animals, who developed ARDS and septic shock with a mortality rate of 75% (S35, Z6). No favorable treatment results have been published yet with one of these treatment modalities given to humans. 

This approach appears somewhat irrational and without much scientific merit, since many of these new molecules are minimally toxic or nontoxic by this sort of acute evaluation. As in the case of interferons or monoclonal antibodies, the toxic effects observed in humans might not be predicted from safety assessments in rodents. An appropriate test species should be selected. Is the rat or mouse the appropriate species to evaluate a species-specific rDNA protein such as human growth hormone or interferons, or would nonhuman primates be more suitable Does the nonhuman primate really offer any advantages There is some consensus that the nonhuman primate may be a more appropriate species for testing some rDNA human proteins. 

With regard to transport capacity, the introduction of the anti-human insulin receptor antibody (HIR MAb) 83-14 as a vector indicates the potential for future improvements in brain-specific delivery vectors. Compared to anti-TfR monoclonal antibodies, the brain de-hvery in primates is over 7-fold higher due to the high PS product of the HIR MAb. 

Biotechnology-derived vaccines that do not induce an immune response in lower species may have to be tested in a primate species, such as the cynomolgus monkey. A study design in the monkey has been suggested for this purpose (6), based on a proposed developmental toxicity study design for monoclonal antibodies (7). 

Chapman K et al (2009) Preclinical development of monoclonal antibodies considerations for the use of non-human primates. MAbs 1 505-516... 

Van der Laan JW, Pentsuk N (2011) ICH S6 regulatory reproduction studies to support the use of monoclonal antibodies. In Weinbauer GF, Vogel F (eds) Future trends in primate toxicology and biotechnology. Waxmann, Muenster, pp 143-162... 

Coloma, M.J., et al. 2000. Transport across the primate blood-brain barrier of a genetically engineered chimeric monoclonal antibody to the human insulin receptor. Pharm Res 17 266. 

There are several relatively new therapeutic modalities for the treatment of SLE. Trying to eliminate pathogenic anti-dsDNAs, Ferguson etal. developed an antigen-based heteropolymer (AHP) (F3). AHP is a bispecific dsDNA x monoclonal antibody (mAb) complex (dsDNA x anti-CRl mAb) that enables the use of the unique immune complex-binding and clearing capacity of the complement receptor (CR1) on primate erythrocytes. In vitro studies of AHP show a substantial reduction (>90%) of anti-dsDNA titer (F20). In vivo studies in two rhesus monkeys indicate that the erythrocyte-bound antibodies are rapidly cleared from the circulation (F3). 

Tesser, J. R. P., Wiesenhutter, C., Levy, R., Schiff, M., Lipani, J., Solinger, A., Mac Donald, B., Elliott, M., and Sing, K (1997). Tratment of rheumatoid arthritis with a primatized anti-CD4 monoclonal antibody, SB-210396 (DEC-CE9.1) Results of an open label extension study in patients responding to induction therapy. Arthritis Rheum. 40 (Suppl 9), S224. 

For most of the other monoclonal antibodies, species cross-reactivity has been limited to nonhuman primates. For these molecules the need to conduct reproductive and developmental studies has to be carefully considered on a case-by-case basis. S5A states that nonhuman primates are best used when the objective of the study is to characterize a relatively certain reproductive toxicant, rather than detect a hazard. The nonhuman primate reproductive toxicity studies are not powered to detect infrequent events. 

Bugelski PJ, Herzyk DJ, Harmsen AG, Gore EV, Williams DM, Maleeff BE, Badger AM, Truneh A, O Brien SR, Macia RA, Wier PJ, Morgan DG, Hart TK. Preclinical development of keliximab, a primatized anti-CD4 monoclonal antibody, in human CD4 transgenic mice characterization of the model and safety studies. Hum Exp Toxicol 2000 19 230 13. 

An other notable example is the work described by Flerzyk et al. [31] where the effects of a Primatized antihuman CD4 monoclonal antibody on experimental metastases with B16 melanoma cells was studied, and an increase in the number of lung colonies was found. Enabling this work, a murine CD4 knockout mouse reconstituted with human CD4 had been described in the literature and was available for license by the sponsor [32], Moreover, in these mice, murine CD4 was faithfully replaced on T cells by human CD4, and the human protein mediated its physiologic function as an accessory binding protein in cellular and humoral immunity. 

Coller BS, Smith SR, Scudder LE et al. (1989) Abolition of in vivo platelet thrombus formation in primates with monoclonal antibodies to the platelet GP Ilb/IIIa receptor correlation with bleeding time, platelet aggregation and blockade of GP Ilb/IIIa receptors. Circulation 80 1766-1774... 

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