Antagonizing the α4ß1 integrin, but not α4ß7, inhibits leukocytic infiltration of the central nervous system in rhesus monkey experimental autoimmune encephalomyelitis.

The immune system is characterized by the preferential migration of lymphocytes through specific tissues (i.e., tissue tropism). Tissue tropism is mediated, in part, by the α(4) integrins expressed by T lymphocytes. The α(4)ß(1) integrin mediates migration of memory T lymphocytes into the CNS, whereas the α(4)ß(7) integrin mediates migration preferentially into gastrointestinal tissue. This paradigm was established primarily from investigations in rodents; thus, the objective of this investigation was to determine if blocking the α(4)ß(7) integrin exclusively would affect migration of T lymphocytes into the CNS of primates. The effects of the dual α(4)ß(1) and α(4)ß(7) antagonist natalizumab were compared with those of the α(4)ß(7) antagonist vedolizumab on experimental autoimmune encephalomyelitis in the rhesus monkey. Animals received an initial i.v. bolus of placebo, natalizumab (30 mg/kg), or vedolizumab (30 mg/kg) before intracutaneous immunization with recombinant human myelin oligodendrocyte glycoprotein and then Ab once weekly thereafter. Natalizumab prevented CNS inflammation and demyelination significantly (p < 0.05), compared with time-matched placebo control animals, whereas vedolizumab did not inhibit these effects, despite saturating the α(4)ß(7) integrin in each animal for the duration of the investigation. These results demonstrate that blocking α(4)ß(7) exclusively does not inhibit immune surveillance of the CNS in primates.

The interleukin-2 antagonizing antibody MT204 delays allogeneic skin graft rejection in non-human primates and is well tolerated.

MT204 is a humanized IgG1 antibody specific for interleukin-2 (IL-2) of human and rhesus monkey origin. It potently antagonizes IL-2 signaling in both CD25(+) and CD25(-) cells by a unique mode of action. MT204 can not only prevent soluble IL-2 from binding to the intermediate affinity IL-2 receptors but can also antagonize IL-2 that is already bound to the CD25 subunit of high affinity IL-2 receptors on the cell surface. As initial steps toward development of a therapeutic antibody, pharmacokinetics (PK) and tolerability of MT204, as well as efficacy were investigated in rhesus monkeys. MT204 was infused by single escalating (2, 10 and 50mg/kg) or repeat dose administrations (50mg/kg, 1 ×/week for 3 weeks). Over the course of the experiment, the animals were regularly observed for clinical adverse reaction and bled for laboratory investigations (PK, hematology, chemical chemistry and leukocyte subset analysis). For the efficacy study, six rhesus monkeys were grafted with MHC-mismatched rhesus skin and infused with MT204 (50mg/kg), on the day of transplantation and again on days 5 and 12 post grafting. Efficacy was determined by assessment of graft necrosis at different time-points. No obvious adverse effects were observed clinically after single infusion, or after three repeated infusions of 50mg/kg and no MT204-related toxic effects were revealed by hematology or clinical chemistry. In the efficacy study, MT204-treated animals showed a significant delay in graft rejection versus control animals (p=0.025 by Log-rank test). The characteristics of MT204, displaying linear pharmacokinetics, half-life in the range expected for a human IgG, benign safety profile and signs of efficacy, warrant further development of this antibody for therapy.