G-CSF/anti-G-CSF antibody complexes drive the potent recovery and expansion of CD11b+Gr-1+ myeloid cells without compromising CD8+ T cell immune responses

Abstract

BackgroundAdministration of recombinant G-CSF following cytoreductive therapy enhances the recovery of myeloid cells, minimizing the risk of opportunistic infection. Free G-CSF, however, is expensive, exhibits a short half-life, and has poor biological activity in vivo.MethodsWe evaluated whether the biological activity of G-CSF could be improved by pre-association with anti-G-CSF mAb prior to injection into mice.ResultsWe find that the efficacy of G-CSF therapy can be enhanced more than 100-fold by pre-association of G-CSF with an anti-G-CSF monoclonal antibody (mAb). Compared with G-CSF alone, administration of G-CSF/anti-G-CSF mAb complexes induced the potent expansion of CD11b+Gr-1+ myeloid cells in mice with or without concomitant cytoreductive treatment including radiation or chemotherapy. Despite driving the dramatic expansion of myeloid cells, in vivo antigen-specific CD8+ T cell immune responses were not compromised. Furthermore, injection of G-CSF/anti-G-CSF mAb complexes heightened protective immunity to bacterial infection. As a measure of clinical value, we also found that antibody complexes improved G-CSF biological activity much more significantly than pegylation.ConclusionsOur findings provide the first evidence that antibody cytokine complexes can effectively expand myeloid cells, and furthermore, that G-CSF/anti-G-CSF mAb complexes may provide an improved method for the administration of recombinant G-CSF.

Developmental Analysis of Bone Marrow Neutrophils Reveals Populations Specialized in Expansion, Trafficking, and Effector Functions

“…For 5-Fluorouracil (5-FU) myeloablative treatment, mice were injected once intraperitoneally with 150mg/kg 5-FU (Sigma-Aldrich) or PBS control. For G-CSF treatment, mice were injected once intraperitoneally with 1.5mg of G-CSF/anti-G-CSF antibody complex (G-CSFcx) as previously described (Rubinstein et al, 2013). Briefly, G-CSFcx were generated by incubating G-CSF (Neupogen) and anti-G-CSF (BVD11-37G10; Southern-Biotech) at 1:5 cytokine to antibody ratio for 20 min at 37 C, and were next diluted at least 10-fold in PBS before injection.…”

Effect of administration timing of postchemotherapy granulocyte colony-stimulating factor on host-immune cell recovery and CD8+ T-cell response

“…The removal of host lymphocytes also allows the accumulation of homeostatic cytokines such as interleukin (IL)-7 and IL-15, and thereby promoting the ability of donor T-cells to mediate anti-tumor immunity (Gattinoni et al 2005). In addition, pre-conditioning a host with CTX can effectively augment the anti-tumor efficacy of adoptively transferred T-cells in response to vaccination (Gattinoni et al 2005, 2006; Wrzesinski et al 2005; Paulos et al 2007; Salem et al 2007, 2009, 2010; Rubinstein et al 2013). …”

“…Studies previously noted that G-CSF administration for 5 consecutive days after CTX treatment can induce transient increases in numbers of dendritic cells (DC) measured on Days 7 and 9 when administered from Days 5–9 as compared to effects when administered Days 1–5 (Salem et al 2010). Importantly, G-CSF administration early after CTX treatment neither alter the expansion of myeloid DC in the blood (Salem et al 2010) nor the expansion of the tumor reactive CD8 + T-cells (Rubinstein et al 2013). …”

IL-2/anti-IL-2 mAb immunocomplexes: A renascence of IL-2 in cancer immunotherapy?

“…Increasing the biological activity of cytokines in vivo via binding to the corresponding anti-cytokine mAb is not a unique phenomenon that is restricted to IL-2. IL-3, 57,58 IL-4, 57 IL-6, 59,60 IL-7 57,61 and GM-CSF 62 complexed with a relevant anticytokine antibody showed superior activity in comparison to free cytokine. IL-5 and IFN-a most likely fall into this category as well, but very limited data that support this are available.…”