Nonclinical reproductive and developmental safety evaluation of the MAGE-A3 Cancer Immunotherapeutic, a therapeutic vaccine for cancer treatment

Destexhe, Éric; Stannard, Diane R.; Wilby, Owen K.; Grosdidier, E.; Baudson, Nathalie; Forster, Roy; Gérard, Catherine; Garçon, Nathalie; Segal, Lawrence

doi:10.1016/j.reprotox.2014.12.009

Cited by 11 publications

(4 citation statements)

References 37 publications

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“…This study adds to the developmental and reproductive toxicity data obtained with BioThrax (Conlin et al, 2017; Franco et al, 2009). The current study also shows that the adjuvant CPG 7909 does not produce any reproductive or developmental toxicity in pregnant rats or their offspring, which is consistent with a previous study in rats (Destexhe et al, 2015).…”

Section: Discussionsupporting

confidence: 93%

Developmental and reproductive safety evaluation of AV7909 anthrax vaccine candidate in rats

Mylchreest

Smiley

Ballin

et al. 2020

Birth Defects Research

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The AV7909 vaccine, consists of the Anthrax Vaccine Adsorbed (AVA) bulk drug substance and the immunostimulatory Toll‐like receptor 9 agonist oligodeoxynucleotide adjuvant CPG 7909. The purpose of this research was to evaluate the potential maternal, reproductive, and developmental toxicity of AV7909 in rats to support licensure for use in women of childbearing potential. Groups of first generation (F0) female Sprague Dawley rats were dosed by intramuscular injection with water for injection, adjuvant or AV7909 at a volume of 0.5 ml/dose. Each rat received three vaccinations: 14 days prior to start of the mating period, on the first day of the mating period and on gestation day (GD) 7. There was no maternal mortality. Body weights, weight gain, and food consumption were comparable between groups. Findings in F0 females were limited to transient injection site edema and nodules consistent with immunostimulatory effects of the vaccine and adjuvant. Administration of AV7909 did not affect mating, fertility, pregnancy, embryo‐fetal viability, growth, or morphologic development, parturition, maternal care of offspring or postnatal survival, growth, or development. There was no evidence of systemic inflammation in pregnant rats, based on evaluation of serum concentrations of the acute phase proteins alpha‐2‐macroglobulin and alpha‐1‐acid glycoprotein on GD 21. Anthrax lethal toxin‐neutralizing antibodies were detected in AV7909‐vaccinated F0 females. The antibodies were also detected in the sera of fetuses and F1 pups. Exposure of the fetuses and pups to maternally derived anthrax lethal toxin‐neutralizing antibodies was not associated with developmental toxicity.

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Section: Discussionsupporting

confidence: 93%

Developmental and reproductive safety evaluation of AV7909 anthrax vaccine candidate in rats

Mylchreest

Smiley

Ballin

et al. 2020

Birth Defects Research

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“…It should be noted that although in a different situation, dosing of rats in a recent combined FD/PPN reproduction toxicology study (with sectioning on day 20 of gestation and littering and observation of offspring until day 25 of age) using a potential therapeutic vaccine (including a immunostimulant adjuvant) for cancer treatment showed an increase in incomplete ossification/unossified of cranial centers from use of the adjuvant (n = 36) among the sectioned fetuses compared to the saline control group (n = 25). 22 The study authors had no specific concern with this finding and reported that there was no indication of reproductive toxicity in this study.…”

Section: Discussionmentioning

confidence: 65%

Effects of the Oral Oxytocin Receptor Antagonist Tocolytic OBE001 on Reproduction in Rats

et al. 2016

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“…Furthermore, we have also previously assessed the effects of AS15 alone or combined with MAGE‐A3 on fertility and pre‐ and postnatal development in rats and monkeys. Similarly, no signs of systemic toxicity were observed after administration of AS15 or MAGE‐A3 + AS15 in these animals (Destexhe et al ., 2014b). …”

Section: Discussionmentioning

confidence: 99%

Non‐clinical safety evaluation of repeated intramuscular administration of the AS15 immunostimulant combined with various antigens in rabbits and cynomolgus monkeys

Garçon

Silvano

Kuper

et al. 2015

J of Applied Toxicology

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Combination of tumor antigens with immunostimulants is a promising approach in cancer immunotherapy. We assessed animal model toxicity of AS15 combined with various tumor antigens: WT1 (rabbits), or p501, dHER2 and recPRAME (cynomolgus monkeys), administered in seven or 20 dose regimens versus a saline control. Clinical and ophthalmological examinations, followed by extensive post‐mortem pathological examinations, were performed on all animals. Blood hematology and biochemistry parameters were also assessed. Antigen‐specific antibody titers were determined by enzyme‐linked immunosorbent assay. Additional assessments in monkeys included electrocardiography and immunohistochemical evaluations of the p501 expression pattern. Transient increases in body temperature were observed 4 h or 24 h after injections of recPRAME + AS15 and dHER2 + AS15. Edema and erythema were observed up to 1 week after most injections of recPRAME + AS15 and all injections of dHER2 + AS15. No treatment‐related effects were observed for electrocardiography parameters. Mean fibrinogen levels were significantly higher in all treated groups compared to controls, but no differences could be observed at the end of the treatment‐free period. Transient but significant differences in biochemistry parameters were observed post‐injection: lower albumin/globulin ratios (p501 + AS15), and higher bilirubin, urea and creatinine (dHER2 + AS15). Pathology examinations revealed significant increases in axillary lymph node mean weights (recPRAME + AS15) compared to controls. A 100% seroconversion rate was observed in all treated groups, but not in controls. p501 protein expression was observed in prostates of all monkeys from studies assessing p501 + AS15. These results suggest a favorable safety profile of the AS15‐containing candidate vaccines, supporting the use of AS15 for clinical development of potential anticancer vaccines. Copyright © 2015 The Authors. Journal of Applied Toxicology Published by John Wiley & Sons Ltd.

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Nonclinical reproductive and developmental safety evaluation of the MAGE-A3 Cancer Immunotherapeutic, a therapeutic vaccine for cancer treatment

Cited by 11 publications

References 37 publications

Developmental and reproductive safety evaluation of AV7909 anthrax vaccine candidate in rats

Developmental and reproductive safety evaluation of AV7909 anthrax vaccine candidate in rats

Effects of the Oral Oxytocin Receptor Antagonist Tocolytic OBE001 on Reproduction in Rats

Non‐clinical safety evaluation of repeated intramuscular administration of the AS15 immunostimulant combined with various antigens in rabbits and cynomolgus monkeys

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