An IL-2/Ig Fusion Protein Influences CD4⁺T Lymphocytes in Naive and Simian Immunodeficiency Virus-Infected Rhesus Monkeys

Abstract

The T cell-stimulatory cytokine interleukin 2 (IL-2) is being evaluated as a therapeutic in the clinical settings of HIV infection and cancer. However, the clinical utility of IL-2 may be mitigated by its short in vivo half-life, toxic effects, and high production costs. We show here that an IL-2/Ig fusion protein possesses IL-2 immunostimulatory activity in vitro and a long in vivo half-life. IL-2/Ig treatment of healthy rhesus monkeys induced significant increases in CD4(+) T lymphocyte counts and expression of CD25 by these cells. Short courses of IL-2/Ig treatment of simian immunodeficiency virus (SIV)-infected rhesus monkeys in conjunction with antiretroviral drugs resulted in increased CD25 expression on T lymphocytes, and transient increases in CD4(+) T lymphocyte counts. Plasma viremia did not increase in these treated animals. Treatment of healthy or SIV-infected rhesus monkeys with a plasmid encoding the IL-2/Ig protein did not affect CD4(+) T lymphocytes. These results demonstrate that IL-2/Ig has potential utility as an immunostimulatory therapeutic.

An IL-7 Fusion Protein That Shows Increased Thymopoietic Ability

“…To help overcome the problem of dosage, chimeric variants of cytokines have been created. These molecules include cytokines conjugated with polyethylene glycol (1) and fusion to albumin (2) or to the Fc portion of IgG (3). Although production of such chimeras prolongs the t 1/2 of cytokines and reduces dosing schedules, it does not completely address the problems associated with improving the cytokine's targeting ability.…”

“…However, treatment with IL-7 is not without its problems: the use of high doses of this cytokine can lead to numerous side effects, such as osteoporosis (11), lymphoma (12), hyperproliferation (12), thrombocytopenia (13), neutropenia (13), and hemolytic anemia (13). In addition, high levels of IL-7 expression have also been shown to inhibit T cell development by inducing a dramatic block in the production of double-positive (DP) 3 cells (14). Phillips et al (15) have attempted to overcome these problems by incorporating an IL-7-secreting stromal cell line into the thymus with some success.…”

Protection against Challenge with Measles Virus (MV) in Infant Macaques by an MV DNA Vaccine Administered in the Presence of Neutralizing Antibody

“…The immune mechanism triggered by the IL-2/IgG molecular adjuvant in this infant macaque vaccine model is not clear. However, in juvenile macaques, a single intramuscular injection of this IL-2/IgG plasmid resulted in transient, low-level increases in peripheral blood CD4 + T cells [31]. We have not measured MV-specific CD4 + T cells in response to DNA vaccination in infant macaques.…”

Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy

“…The effect is fundamentally different than a slow release of free-IL2 from a formulated matrix [30, 31] or from free-IL2 linked to an Fc to improve t ½ [32, 33]. Therefore, we developed specialized bioanalytical assays to characterize relevant groups of conjugated-IL2 species derived from NKTR-214.…”

“…-IL2 release from such a matrix does not create an array of conjugated-IL2 species such as that produced from NKTR-214 in vivo . As described, matching the theoretical exposure of IL2 to that of NKTR-214 does not result in the biased receptor occupancy achieved by NKTR-214 [32, 33]. Moreover, these IL2 formulations, Fc fusions, or antibody complexes immediately deliver active IL2 to the system, potentially increasing toxicities.…”