title: Non-clinical safety evaluation of single and repeated intramuscular administrations of MAGE-A3 Cancer Immunotherapeutic in rabbits and cynomolgus monkeys.
abstract: The MAGE-A3 recombinant protein combined with AS15 immunostimulant (MAGE-A3 Cancer Immunotherapeutic) is under development by GlaxoSmithKline for the treatment of lung cancer and melanoma. We performed non-clinical safety studies evaluating potential local and systemic toxic effects induced by MAGE-A3 Cancer Immunotherapeutic in rabbits (study 1) and cynomolgus monkeys (study 2). Animals were allocated to two groups to receive a single (rabbits) or 25 repeated (every 2 weeks) injections (monkeys) of MAGE-A3 Cancer Immunotherapeutic (treatment groups) or saline (control groups). All rabbits were sacrificed 3 days post-injection and monkeys 3 days following last injection (3/5 per gender per group) or after a 3-month treatment-free period (2/5 per gender per group). Local and systemic reactions and MAGE-A3-specific immune responses (monkeys) were assessed. Macroscopic and microscopic (for rabbits, injection site only) post-mortem examinations were performed on all animals. No systemic toxicity or unscheduled mortalities were recorded. Single (rabbits) and repeated (monkeys; up to four times at the same site) injections were well tolerated. Following five to seven repeated injections, limb circumferences increased up to 26% (5 h post-injection), but returned to normal after 1-8 days. Three days after the last injection, enlargements of iliac, popliteal, axillary and inguinal lymph nodes, and increased incidence or severity of mononuclear inflammatory cell infiltrates was observed in injected muscles of treated monkeys. No treatment-related macroscopic findings were recorded after the treatment-free period. MAGE-A3-specific antibody and T-cell responses were raised in all treated monkeys, confirming test item exposure. Single or repeated intramuscular injections of MAGE-A3 Cancer Immunotherapeutic were well tolerated in rabbits and monkeys.
authors.affiliation: GlaxoSmithKline Vaccines, 1330, Rixensart/Wavre, Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Destexhe
authors.affiliation: CiToxLAB France, 27005, Evreux, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Grosdidier
authors.affiliation: GlaxoSmithKline Vaccines, 1330, Rixensart/Wavre, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Baudson
authors.affiliation: CiToxLAB France, 27005, Evreux, France.
authors.forename: Roy
authors.initials: R
authors.lastname: Forster
authors.affiliation: GlaxoSmithKline Vaccines, 1330, Rixensart/Wavre, Belgium.
authors.forename: Catherine
authors.initials: C
authors.lastname: Gerard
authors.affiliation: GlaxoSmithKline Vaccines, 1330, Rixensart/Wavre, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Garçon
authors.affiliation: GlaxoSmithKline Vaccines, 1330, Rixensart/Wavre, Belgium.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Segal
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D007167:Immunotherapy / Q000379:methods; D007273:Injections, Intramuscular; D008252:Macaca fascicularis; D008297:Male; D009363:Neoplasm Proteins / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy; D011817:Rabbits; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology
chemical_list: D000951:Antigens, Neoplasm; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins
keywords: MAGE-A3 Cancer Immunotherapeutic; animal model; monkey; non-clinical study; rabbit; repeated dose; single dose; toxicology