A recombinant antibody-interleukin 2 fusion protein suppresses growth of hepatic human neuroblastoma metastases in severe combined immunodeficiency mice.

Abstract

A genetically engineered fusion protein consisting of a human/mouse chimeric anti-ganglioside GD2 antibody (chl4.18) and recombinant human interleukin 2 (rhIL-2) was tested for its ability to target rhIL-2 to tumor sites and stimulate immune effector cells sufficiently to achieve effective tumor cell lysis in vivo. The chl4.18-IL-2 fusion protein proved more effective than equivalent doses of rhIL-2 in suppressing dissemination and growth of human neuroblastoma in an experimental hepatic metastases model of scid (severe combined immunodeficiency) mice reconstituted with human lymphokine-activated killer cells. The chl4.18-IL-2 fusion protein was also more proficient than equivalent doses of rhIL-2 in prolonging the life-span of these animals. This recombinant antibody-cytokine fusion protein may prove useful for future treatment ofGD2-expressing human tumors in an adjuvant setting.

Cytokine therapy: clinical and progressive status in cancer

“…Early studies focused on establishing the biological functionality of the immunocytokine and on determining whether the fused protein retained full antibody and cytokine functions. That ch14.18-IL-2 retains its functionality as an antibody was confirmed by the finding that the immunocytokine and ch14.18 had comparable GD2-binding patterns in direct binding assays with human neuroblastoma cells (Sabzevari et al, 1994). Dissociation constants (Kd) for the immunocytokine and ch14.18 were 24 nM and 18 nM, respectively.…”

Anti-GD2 MABS and Next-Generation mAb-Based Agents for Cancer Therapy

“…When tested in mice, pharmacokinetics studies demonstrated that fusion protein prolonged the half-life of IL2 when compared with soluble IL2, highlighting the potential for ch14.18-IL2 to lead to more efficient IL2-induced immune cell activation in vivo [89]. Moreover, ch.14.18-IL2 demonstrated superior antitumor effects when compared with equivalent amounts of the ch14.18 or hu14.18 mAb and IL2 administered simultaneously as separate agents [87,90,91]. The promising preclinical data with ch14.18-IL2 led to the development of a hu14.18-IL2, a humanized IC, to recapitulate in patients the antitumor effects observed with ch14.18-IL2 while minimizing the immunogenicity associated with the chimeric mAb [92].…”

“…ch14.18-IL2 is able to bind GD2 expressed on the surface of cells indicating that it retains its antigen binding ability and can effectively target IL2 to the tumor site leading to tumor lysis [87]. In vitro analyses showed that ch14.18-IL2 activated human effector cells to the same extent as soluble human IL2 and was able to mediate ADCC effectively; demonstrating that both the IL2 and Fc components of the fusion protein remained intact and able to interact with their respective receptors [86,88].…”

Novel Therapeutic Approaches for Neuroblastoma

“…To date, immunocytokine research has focused on ADCC mediated by NK cells and on induction of CTL. An anti-GD2/IL-2 immunocytokine eradicated hepatic metastases of neuroblastomas in SCID mice that had been reconstituted with human lymphokine (IL-2) activated killer cells [153,154]. In contrast, the combination of monoclonal anti-GD2 antibody and IL-2 at doses equivalent to the immunocytokine only reduced tumor load.…”