Placental transfer of 125iodinated humanized immunoglobulin G2Δa in the cynomolgus monkey
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30 Abstracts / Reproductive Toxicology 48 (2014) 23–36 chroride-1-hydrate during gestation. Preliminary study. Reprod Toxicol 2012;34(2):164. Bousnaki M, Makaronidis I, Sioga A, Simou C, Nikolousis E, Kon- stantinidou E, Kaidoglou K, Papamitsou T, Emmanouil-Nikoloussi E-N. Ultrastructural observations of brain neurotoxicity in neonatal mice after “in vivo” individual exposure to arsenic and lead during gestation. Reprod Toxicol 2013;41:29. http://dx.doi.org/10.1016/j.reprotox.2014.07.045 P-18 Placental transfer of 125 iodinated humanized immunoglobulin G2a in the cynomolgus monkey Christopher J. Bowman 1,∗ , Andrea Z. Mitchell 2 , Michael J. Potchoiba 2 , Denise M. O‘Hara 3 , Mengmeng Wang 3 , Jeffrey Kurz 3 , Minlei Zhang 3 , Susan Henwood 2 1 Pfizer, Inc., Groton, CT, USA 2 Covance Laboratories, Inc., Madison, WI, USA 3 Pfizer Inc., Andover, MA, USA Introduction: Antibody-like biopharmaceuticals cross the pla- centa by utilizing transport pathways available for transfer of maternal antibodies to the conceptus. Previous work has demon- strated placental transfer of humanized immunoglobulins (IgG) in the rat starting during organogenesis. Little is known about placen- tal transfer of these molecules in primates (humans or monkeys). Methods: To characterize the timing and magnitude of this trans- fer in the cynomolgus monkey, embryo/fetal biodistribution of maternally administered radiolabeled humanized IgG2 was quanti- fied on gestation days 35, 40, 50, 70 and 140 using gamma counting and whole body autoradiography 24 h following intravenous injec- tion. Results: Following maternal administration, humanized IgG2 was found in monkey embryo/fetal tissues and plasma at all time- points evaluable, including during organogenesis. Embryo/fetal tissue concentrations were much lower than embryo/fetal plasma concentrations which were markedly lower than maternal plasma concentrations. IgG2 concentration increased with gestation in embryo/fetal plasma. However, in embryo/fetal tissues, IgG2 con- centration only slightly increased up to gestation day 70 but was generally similar on gestation days 70 and 140. Placental FcRn protein expression was confirmed at all timepoints. The embryo/fetal:maternal plasma concentration ratio of IgG2 was approximately 2.3 fold higher on gestation day 140 when compared with those ratios on gestation day 40. The embryo/fetal concentra- tion of radiolabeled humanized IgG2 in the nonhuman primate was generally similar to that observed in rat under similar experimental conditions. Conclusions: These data demonstrate that embryo/fetal con- centrations of humanized IgG2 in nonhuman primate are similar to previous data in the rat, demonstrating that rat represents a biologically relevant species for placental transfer of humanized IgG2. Based on the empirical amount of antibody present in the nonhuman primate and rat embryo/fetus during specific develop- mental windows including organogenesis, direct antibody binding to biological targets present in the developing conceptus could potentially result in adverse developmental outcomes. http://dx.doi.org/10.1016/j.reprotox.2014.07.046 P-19 Combination effects on reproductive endpoints in male rats perinatally exposed to a mixture of anti-androgens and oestrogens Sofie Christiansen ∗ , Marta Axelstad, Karen R. Mandrup, Julie Boberg, Ulla Hass Division of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Denmark Exposure to endocrine disrupting chemicals during develop- ment can affect sexual differentiation, thereby causing permanent reproductive changes throughout life. Humans may daily be exposed to a complex mixture of endocrine disrupters (EDs). Even though risk assessment of chemicals is still primarily done for one chemical at a time, regulatory focus has begun shifting towards assessing the effects of exposure to mixtures of EDs. The aim of this project was to investigate whether exposure of rats to mix- tures of EDs with dissimilar modes of action, i.e. anti-androgenic and oestrogenic, during prenatal and early postnatal development, would cause mixture effects. Moreover, the aim was to provide important knowledge on mixture effects for regulatory use, espe- cially for considerations regarding grouping of EDs for cumulative risk assessment. Seven groups of time-mated Wistar rats (n = 15–18) were gav- aged from gestation day 7 to pup day (PD) 16 with different mixtures of EDs, and anogenital distance (AGD), nipple retention and reproductive organs weights were assessed in the neonatal male offspring. The seven dose groups were: vehicle control, two doses of an anti-androgen mixture consisting of DEHP and procymidone (Amix1, Amix2), two doses of an oestrogen mixture consisting of bisphenol A and butylparaben (Emix1, Emix2) and two doses with a combination of all four compounds (AEmix1, AEmix2). Previous studies with perinatal exposure to each of the single compounds showed that they could all reduce male AGD at birth, but that the maximum response for the anti-androgens was much larger than for the oestrogens. The dose levels for the mixtures were chosen based on the single chemicals’ potency to reduce AGD. Both doses of the AEmix and the Amix2 significantly decreased AGD at birth in male offspring, compared to controls. Nipple reten- tion on PD 14 in male offspring was significantly increased in the groups exposed to either of the doses of AEmix or of Amix. Weights of testes, epididymides and ventral prostate were affected by AEmix and Amix and weights of levator ani/bulbocavernosus muscles (LABC) and bulbourethral glands were decreased by one or both doses of all mixtures. The combined exposure to both anti- androgens and oestrogens lead to mixture effects for AGD, nipple retention and some male reproductive organ weights PD16. In most cases, the mixture effect was seen as more marked effects in the groups exposed to both anti-androgens and oestrogens than in the groups exposed only to the anti-androgens or only to the oestro- gens. These findings show that chemicals with dissimilar modes of action can lead to combination effects and indicate that grouping criteria should focus on common adverse health outcomes. Using only mechanisms of action as the starting point for grouping of endocrine disrupters is insufficient, when cumulative risk assess- ment is performed. http://dx.doi.org/10.1016/j.reprotox.2014.07.047
Transcript of Placental transfer of 125iodinated humanized immunoglobulin G2Δa in the cynomolgus monkey
30 Abstracts / Reproductive Toxicology 48 (2014) 23–36
chroride-1-hydrate during gestation. Preliminary study. ReprodToxicol 2012;34(2):164.
Bousnaki M, Makaronidis I, Sioga A, Simou C, Nikolousis E, Kon-stantinidou E, Kaidoglou K, Papamitsou T, Emmanouil-NikoloussiE-N. Ultrastructural observations of brain neurotoxicity in neonatalmice after “in vivo” individual exposure to arsenic and lead duringgestation. Reprod Toxicol 2013;41:29.
http://dx.doi.org/10.1016/j.reprotox.2014.07.045
P-18
Placental transfer of 125iodinated humanizedimmunoglobulin G2�a in the cynomolgusmonkey
Christopher J. Bowman 1,∗, Andrea Z. Mitchell 2,Michael J. Potchoiba 2, Denise M. O‘Hara 3,Mengmeng Wang 3, Jeffrey Kurz 3, Minlei Zhang 3,Susan Henwood 2
1 Pfizer, Inc., Groton, CT, USA2 Covance Laboratories, Inc., Madison, WI, USA3 Pfizer Inc., Andover, MA, USA
Introduction: Antibody-like biopharmaceuticals cross the pla-centa by utilizing transport pathways available for transfer ofmaternal antibodies to the conceptus. Previous work has demon-strated placental transfer of humanized immunoglobulins (IgG) inthe rat starting during organogenesis. Little is known about placen-tal transfer of these molecules in primates (humans or monkeys).
Methods: To characterize the timing and magnitude of this trans-fer in the cynomolgus monkey, embryo/fetal biodistribution ofmaternally administered radiolabeled humanized IgG2 was quanti-fied on gestation days 35, 40, 50, 70 and 140 using gamma countingand whole body autoradiography 24 h following intravenous injec-tion.
Results: Following maternal administration, humanized IgG2was found in monkey embryo/fetal tissues and plasma at all time-points evaluable, including during organogenesis. Embryo/fetaltissue concentrations were much lower than embryo/fetal plasmaconcentrations which were markedly lower than maternal plasmaconcentrations. IgG2 concentration increased with gestation inembryo/fetal plasma. However, in embryo/fetal tissues, IgG2 con-centration only slightly increased up to gestation day 70 butwas generally similar on gestation days 70 and 140. PlacentalFcRn protein expression was confirmed at all timepoints. Theembryo/fetal:maternal plasma concentration ratio of IgG2 wasapproximately 2.3 fold higher on gestation day 140 when comparedwith those ratios on gestation day 40. The embryo/fetal concentra-tion of radiolabeled humanized IgG2 in the nonhuman primate wasgenerally similar to that observed in rat under similar experimentalconditions.
Conclusions: These data demonstrate that embryo/fetal con-centrations of humanized IgG2 in nonhuman primate are similarto previous data in the rat, demonstrating that rat represents abiologically relevant species for placental transfer of humanizedIgG2. Based on the empirical amount of antibody present in thenonhuman primate and rat embryo/fetus during specific develop-mental windows including organogenesis, direct antibody bindingto biological targets present in the developing conceptus couldpotentially result in adverse developmental outcomes.
http://dx.doi.org/10.1016/j.reprotox.2014.07.046
P-19
Combination effects on reproductive endpointsin male rats perinatally exposed to a mixture ofanti-androgens and oestrogens
Sofie Christiansen ∗, Marta Axelstad, Karen R.Mandrup, Julie Boberg, Ulla Hass
Division of Toxicology and Risk Assessment, NationalFood Institute, Technical University of Denmark,Denmark
Exposure to endocrine disrupting chemicals during develop-ment can affect sexual differentiation, thereby causing permanentreproductive changes throughout life. Humans may daily beexposed to a complex mixture of endocrine disrupters (EDs). Eventhough risk assessment of chemicals is still primarily done for onechemical at a time, regulatory focus has begun shifting towardsassessing the effects of exposure to mixtures of EDs. The aim ofthis project was to investigate whether exposure of rats to mix-tures of EDs with dissimilar modes of action, i.e. anti-androgenicand oestrogenic, during prenatal and early postnatal development,would cause mixture effects. Moreover, the aim was to provideimportant knowledge on mixture effects for regulatory use, espe-cially for considerations regarding grouping of EDs for cumulativerisk assessment.
Seven groups of time-mated Wistar rats (n = 15–18) were gav-aged from gestation day 7 to pup day (PD) 16 with differentmixtures of EDs, and anogenital distance (AGD), nipple retentionand reproductive organs weights were assessed in the neonatalmale offspring.
The seven dose groups were: vehicle control, two doses ofan anti-androgen mixture consisting of DEHP and procymidone(Amix1, Amix2), two doses of an oestrogen mixture consisting ofbisphenol A and butylparaben (Emix1, Emix2) and two doses witha combination of all four compounds (AEmix1, AEmix2). Previousstudies with perinatal exposure to each of the single compoundsshowed that they could all reduce male AGD at birth, but that themaximum response for the anti-androgens was much larger thanfor the oestrogens. The dose levels for the mixtures were chosenbased on the single chemicals’ potency to reduce AGD.
Both doses of the AEmix and the Amix2 significantly decreasedAGD at birth in male offspring, compared to controls. Nipple reten-tion on PD 14 in male offspring was significantly increased inthe groups exposed to either of the doses of AEmix or of Amix.Weights of testes, epididymides and ventral prostate were affectedby AEmix and Amix and weights of levator ani/bulbocavernosusmuscles (LABC) and bulbourethral glands were decreased by oneor both doses of all mixtures. The combined exposure to both anti-androgens and oestrogens lead to mixture effects for AGD, nippleretention and some male reproductive organ weights PD16. In mostcases, the mixture effect was seen as more marked effects in thegroups exposed to both anti-androgens and oestrogens than in thegroups exposed only to the anti-androgens or only to the oestro-gens. These findings show that chemicals with dissimilar modes ofaction can lead to combination effects and indicate that groupingcriteria should focus on common adverse health outcomes. Usingonly mechanisms of action as the starting point for grouping ofendocrine disrupters is insufficient, when cumulative risk assess-ment is performed.
http://dx.doi.org/10.1016/j.reprotox.2014.07.047
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