Enhancement of anti-tumor activity of recombinant interleukin-2 (rIL-2) by immunocomplexing with a monoclonal antibody against rIL-2

Abstract

We have investigated biological properties of an immune complex of recombinant interleukin-2 (rIL-2) and a monoclonal antibody against rIL-2 in mice for induction of killer cells and for anti-tumor activity. We have also examined the clearance of subcutaneously-injected immune complex in mice and compared it with that of rIL-2 alone. Plasma rIL-2 levels were sustained longer in mice given the immune complex than in mice given rIL-2 alone at a dose of 10 micrograms/mouse, and they were detectable even at 24 hours after the administration of the immune complex, while they fell to undetectable levels by 6 hours after the administration of rIL-2 alone. A more significant portion of rIL-2 was detected in lymph nodes after subcutaneous injection of the immune complex than that of rIL-2 alone. Splenic lymphocytes from mice given the immune complex demonstrated a higher killer cell activity against YAC-1 cells than those from mice given rIL-2 alone. The immune complex also exerted more significant anti-tumor effect in a dose-dependent manner in Meth-A fibrosarcoma-bearing mice than rIL-2 alone. Our results indicate that immunocomplexing of rIL-2 with an antibody against rIL-2 provides a useful tool as the drug delivery system for cancer therapy using rIL-2.

IL-7/Anti-IL-7 mAb Complexes Restore T Cell Development and Induce Homeostatic T Cell Expansion without Lymphopenia

“…However, it is possible that the neonatal Fc receptors, which are involved in prolonging the half-life of IgG (65,66), could play an important role. Past reports have ascribed an increased in cytokine half-life as the main mechanism behind the intense activity of cytokine/mAb complexes (15,16,(61)(62)(63). This idea is supported by the finding that IL-7/M25 complexes survived functionally for ϳ24 h, much longer than the ϳ20-min half-life typically assigned to free cytokines (14,64).…”

“…The ability of specific anti-cytokine mAbs to dramatically boost the in vivo activity of the bound cytokines was initially recognized in the early 1990s. This applied to several cytokines, including IL-2, IL-3, IL-4, IL-6, and IL-7 (15,16,(61)(62)(63). Nonetheless, the potential utility of cytokine/mAb complexes remained largely unexplored.…”

Effector/memory T cells of the weanling mouse exhibit Type 2 cytokine polarization in vitro and in vivo in the advanced stages of acute energy deficit

“…No in vivo index of cytokine production can be independent of physiological turnover, a potentially crippling confounder in relation to blood cytokines because of their brief half-lives that are generally measured in minutes [33][34][35][36]. The in vivo cytokine capture assay traps newly synthesized cytokine in an antibody complex that extends the half-life of the bound cytokine to hours or days in the blood of the mouse [34,[36][37][38][39].…”

IL-2/Anti-IL-2 Antibody Complex Enhances Vaccine-Mediated Antigen-Specific CD8+ T Cell Responses and Increases the Ratio of Effector/Memory CD8+ T Cells to Regulatory T Cells

“…Increases in the stability of complexed IL-2, IL-3, IL-4, IFN-␣, and IL-6 (13)(14)(15)(16)(17)(18)(19)(20)(21) and in the biological activity of the cytokine complex for IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IFN-␥, and TNF (2, 5, 16 -29) have been demonstrated. In addition to these complexes formed with Ab, recent studies established the increase of biological activity of IL-15 complexed with the IL-15 receptor chain ␣ (30,31).…”