Safety, Pharmacokinetics, and Biological Pharmacodynamics of the Immunocytokine EMD 273066 (huKS-IL2)

Abstract

This phase 1 clinical trial was conducted to evaluate the safety and to determine the maximum tolerated dose (MTD) of the immunocytokine EMD 273066 huKS-IL2 and, secondarily, to assess its pharmacokinetics, immunogenic potential, and immunologic activity in patients with androgen-independent prostate cancer (n = 22). EMD 273066 was administered in 3-day cycles (separated by 4 weeks) of once-daily, 4-hour intravenous infusions at a dose determined by an escalation protocol (0.4, 0.7, 1.4, 2.8, 4.3, 6.4, or 8.5 mg/m/d). Approximately 2/3 of patients received a second cycle of treatment. The results show that the MTD of EMD 273066 [ie, one dose level below that producing dose-limiting toxicity (DLT) in at least 33% of patients in a dosing group] was 6.4 mg/m/d. EMD 273066 was generally well tolerated up to a dose of 4.3 mg/m/d. No DLTs, defined as drug-related toxicities >OR= Grade 3 occurring during the first treatment cycle, were observed among patients in the 0.4-, 0.7-, 1.4-, or 4.3-mg/m/d dosing groups. Four patients treated with 2.8, 6.4, or 8.5 mg/m/d EMD 273066 experienced DLTs. Titers of both antiimmunocytokine and anti-FcIL-2 antibody responses were observed after the first dose cycle and either decreased or remained stable during a second course of treatment. No hypersensitivity reactions were observed. EMD 273066 exhibited immunologic activity as demonstrated by increases in lymphocyte counts, natural killer cell number and specific activity, and antibody-dependent cellular cytotoxicity activity. On average, Cmax, which was dose-dependent, was achieved within 1 hour after infusion. Mean t(1/2) which was independent of dose, ranged from 4.0 to 6.7 hours across doses. A zero-compartment body model with one-order kinetics best described the concentration-time profiles. These data demonstrate that the novel immunocytokine EMD 273066 is well tolerated at doses above a level of observed systemic biologic activity in patients with androgen-independent prostate cancer.

Intratumoral immunocytokine treatment results in enhanced antitumor effects

“…ICs are synthetic proteins that combine both of these strategies via a tumor antigen-specific mAb fused to an immune-stimulating cytokine. Members of this novel class of immunotherapy have been shown to have significant antitumor and antimetastatic effects in several murine tumor models and are currently being investigated for clinical safety and anticancer potential in human patients with neuroblastoma (NB), melanoma, ovarian and prostate cancers [8,[21][22]32]. Our laboratories have been involved in the preclinical and clinical development of two ICs [39]: huKS-IL2, which consists of the humanized mAb huKS1/4 that recognizes epithelial cell adhesion molecule (EpCAM) and is linked to IL2; and hu14.18-IL2, which is an anti-disialoganglioside GD 2 mAb also linked to IL2.…”

Antibody–cytokine fusion proteins: applications in cancer therapy

“…Additionally these patients showed titers of anti-antibody-(IL-2) fusion protein, but no hypersensitivity reactions were observed. In general, EMD 273066 was well tolerated without any further effects beyond those expected for high dose IL-2 administration alone [107]. EMD 273066 has also demonstrated high specificity for EpCAM in biopsies from women with ovarian cancer [108].…”

“…HuKS-(IL-2) (huKS1/4-(IL-2): EMD 273066) has been evaluated in Phase I clinical trials conducted in patients with androgen-independent prostate cancer treated with a continuous 4-h intravenous infusion at the dose determined by an escalation protocol [107]. EMD 273066 demonstrated immunological activity, as measured by the increase in lymphocyte counts, NK-activity, NK cell numbers and ADCC activity [107].…”

“…HuKS-(IL-2) (huKS1/4-(IL-2): EMD 273066) has been evaluated in Phase I clinical trials conducted in patients with androgen-independent prostate cancer treated with a continuous 4-h intravenous infusion at the dose determined by an escalation protocol [107]. EMD 273066 demonstrated immunological activity, as measured by the increase in lymphocyte counts, NK-activity, NK cell numbers and ADCC activity [107]. The maximum tolerated dose was 6.4 mg/m 2 /dose and the mean half-life was dose-independent, in the range of 4.0 -6.7 h. Patients treated with this antibody-cytokine fusion protein experienced toxic side effects associated with the toxic effects of IL-2 such as rigors, chills and anemia [107].…”

“…EMD 273066 demonstrated immunological activity, as measured by the increase in lymphocyte counts, NK-activity, NK cell numbers and ADCC activity [107]. The maximum tolerated dose was 6.4 mg/m 2 /dose and the mean half-life was dose-independent, in the range of 4.0 -6.7 h. Patients treated with this antibody-cytokine fusion protein experienced toxic side effects associated with the toxic effects of IL-2 such as rigors, chills and anemia [107]. Additionally these patients showed titers of anti-antibody-(IL-2) fusion protein, but no hypersensitivity reactions were observed.…”