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

Abstract

<jats:p> Keliximab is a human-cynomolgus monkey chimeric (Primatized) monoclonal antibody with specificity for human and chimpanzee CD4. As the preclinical safety assessment of biopharmaceuticals requires evaluation in pharmacologically responsive species, comprehensive toxicology studies, including reproductive toxicity, of this antibody were conducted in a human CD4 transgenic mouse model. The reproductive toxicology studies included a preand postnatal development study that incorporated immunotoxicological evaluation of offspring (F1) mice. The potential effects of exposure to treating maternal mice (F0) with keliximab during pregnancy and lactation on offspring viability, physical growth, neurobehavioral development, reproductive function, lymphoid tissue morphological structure, lymphocyte subsets and host resistance to Candida albicans infection were assessed. The results showed no impairment of these functions. The use of F1 transgenic mice in study with keliximab provides an example of a novel practical approach to assess developmental immunotoxicity within a study of preand postnatal development designed in accordance with ICH Guidelines. </jats:p>

Species comparison of anatomical and functional immune system development

“…One of the most important questions considered in the workshops was how to determine the most appropriate species and strains to model the developing human immune system. A workshop organized by ILSI HESI in 2001 considered the following animal models in a series of plenary presentations: mice (Landreth, 2002;Herzyk et al, 2002;Holladay and Blalock, 2002), rats (Smialowicz, 2002;Chapin, 2002), pigs (Rothkotter et al, 2002), dogs (Felsburg, 2002) and nonhuman primates (Hendrickx et al, 2002;Neubert et al, 2002), in addition to humans (Neubert et al, 2002;West, 2002). A subsequent panel discussion, with input from all participants, offered several important conclusions (Holsapple, 2002a).…”

Embryonic and fetal programming of physiological disorders in adulthood

“…Biochemical changes induced by prenatal insults that lead to physiological deficits of organ function may not always be accompanied by detectable anatomical abnormalities. Hence, in recent decades, considerable attention has been drawn to functional teratology, an extension of the investigation beyond morphological examinations to include the evaluations of functional integrity of organ systems (for examples, see Kavlock and Grabowski, 1983;Lau and Kavlock, 1994;Herzyk et al, 2002). Nonetheless, a majority of these works has focused primarily on the perinatal and early postnatal periods, and long-term follow-up studies are seldom available.…”

Genetically Modified Animals in Pharmacology and Toxicology Research: Review

“…19 Gü-nümüze kadar IL-12p40 knock-out, IL-6 knock-out ve HuCD4 transgenik farelerin gelişme ve üreme toksikolojisi çalışmalarında başarıyla kullanıldığı belirtilmiştir. 19,[64][65][66] İyi çalışma şartlarına uygun laboratuvarlarda günümüze kadar juvenil toksikoloji araştırmala-rında genetiği değiştirilmiş hayvanların kullanıldı-ğına ilişkin bir çalışmaya rastlanmamıştır.…”