Under tissue remodeling conditions, mechanisms of alternative splicing can lead to the insertion of EDB, an extra 91-amino-acid type III homology domain, into fibronectin (Figure 2B).43,44 In healthy individuals, EDB is undetectable, but in many aggressive solid tumors EDB is highly expressed around tumor vasculature.45C48 Rabbit Polyclonal to c-Jun (phospho-Ser243) Furthermore EDB is identical in mouse, rat, rabbit, dog, monkey, and man.43 The high-affinity antibody L19 recognizes EDB and has been shown to efficiently localize to tumor blood vessels in animal models and cancer patients.26,49C53 Tenascin C A1 domain Tenascins are glycoproteins found in the extracellular matrix of vertebrates. for therapeutic applications. Ever since the approval in 1995 of the first recombinant cytokine (interferon [IFN]-2) for the treatment of malignant melanoma, interest in cytokines for cancer therapy has increased.1 To date, a number of immunostimulatory cytokines, which have shown beneficial effects in preclinical animal models of cancer and in clinical studies, have received marketing authorization (eg, interleukin [IL]-2 [Proleukin?, Aldesleukin?; Novartis, Basel, Switzerland], tumor necrosis factor [TNF]- [Beromun?; Boehringer Ingelheim, Ingelheim am Rhein, Germany], interferon [IFN]-2 [Roferon-A?; Hoffmann-La Roche, Basel, Switzerland, Intron-A?; Merck & Co., Whitehouse Station, NJ, USA], and granulocyte-macrophage colony-stimulating factor [GMCSF] [Leukine?; Genzyme, Cambridge, MA, USA, Leucomax?; Novartis, Basel, Switzerland]). In addition, immunosuppressive and immunomodulatory cytok-ines (eg, IL-4 and IL-10) have been considered for treatment of rheumatoid arthritis, psoriasis, and inflammatory bowel disorders. At present, only a handful of cytokines is in active clinical development. Tumor eradication has been achieved in models of cancer by intratumoral or peritumoral application of cytokines or by implantation of tumor cells expressing cytokines.2C6 Yet, these techniques are not readily applicable in the clinical setting, particularly 2,4-Diamino-6-hydroxypyrimidine in consideration of the fact that cancer is often a disseminated disease. Systemic administration of cytokines, on the other hand, rarely results in complete cures, and dose escalation is hindered by dose-limiting toxicities (DLTs), which in turn prevent the administration of potentially curative regimens. These observations indicate that cytokines are potent modulators of the immune system that can eradicate tumors if high enough concentration is achieved at the site 2,4-Diamino-6-hydroxypyrimidine of disease. With the introduction of monoclonal antibody engineering technology and the identification of tumor-specific and accessible antigens, the targeted delivery of cytokines has become possible. Indeed, the use of antibodyCcytokine fusion proteins (immunocytokines) has the potential to improve the therapeutic index of cytokines by concentrating the payload at the site of localized or disseminated disease, thus reducing side effects. A prominent example is represented by the antibody-mediated targeted delivery of IL-12, which has been shown to be at least 20 times more potent than untargeted IL-12 (ie, has achieved a better therapeutic activity at less than 1/20th of the dose of 2,4-Diamino-6-hydroxypyrimidine the unmodified cytokine) in a mouse model of cancer.7 While good reviews exist on the topic of immunocytokines, this work focuses on immunocytokines that have reached clinical development (Table 1), aiming to provide an overview of the preclinical data that has led to clinical trials and of rising clinical outcomes.8C11 Desk 1 Summary of the immunocytokines in clinical advancement thead th align=”still left” valign=”best” rowspan=”1″ colspan=”1″ Immunocytokine /th th align=”still left” valign=”best” rowspan=”1″ colspan=”1″ Firm /th th align=”still left” valign=”best” rowspan=”1″ colspan=”1″ Structure /th th align=”still left” valign=”best” rowspan=”1″ colspan=”1″ Illustration /th th align=”still left” valign=”best” rowspan=”1″ colspan=”1″ Antigen /th th align=”still left” valign=”best” rowspan=”1″ colspan=”1″ Sign /th th align=”still left” valign=”best” rowspan=”1″ colspan=”1″ Stage /th th align=”still left” valign=”best” rowspan=”1″ colspan=”1″ Preclinical efficacy /th th align=”still left” valign=”best” rowspan=”1″ colspan=”1″ Recommended dosage in the clinic /th /thead F16-IL2 (Teleukin)PhilogenDiabody Open up in another window AI domains of Tenascin CBreast cancers, lung cancerPhase Ib/11AE w/doxorubicin, AE w/paclitaxel, CC xeno w/temozolomide25 Mio IU (1.6 mg) iv 1 weekly with 25 mg/m2 paclitaxel up to six months br / Dosage even now escalatingHu14.l8-IL2 br / (EMD273063)Merck KGaAIgG Open up in another screen GD2Melanoma, neuroblastomaPhase IICh 14.18-IL2: AE+ (metastatic foci) xeno, AE+ (metastatic foci) syng, VE br / Hu14.18-IL2:AE syng7.5 mg/m2 iv (melanoma) br / 12.5 mg/m2 iv (neuroblastoma) br / 3 weekly for three cycles (3 weeks)L19-IL2 br / 2,4-Diamino-6-hydroxypyrimidine (Darleukin)PhilogenDiabody Open up in another window EDB FibronectinMelanoma, pancreas, RCCPhase IIbCC xeno w/rituximab, CC syng w/anti-CTLA4 or L19-TNF, VE br / AE xeno (orthopic pancreatic cancer model) br / AE syng22.5 Mio IU ( 1.38 mg) iv 3 weekly with or without 1 g/m2 dacarbazine br / Ongoing research on extra escalation (regular timetable)NHS-IL2LT br / (EMD 521873, Selectikine)Merck KGaAIgG Open up in another screen DNASolid tumors, NH lymphoma, NSCL carcinomaPhase I/IIAE+ syng0.6 mg/kg iv 3 every 3 weeks with 300 mg/m2 cyclophosphamideBCI-IL12 br / (AS 1409)Antisoma/NovartisIgG Open up in another window Domains VII of FibronectinMelanomaPhase I/IIAE+ xeno (metastatic foci)15 g/kg iv 1 weekly for 6 weeksNHS-IL12 br / (hTNT3-IL12, MSB0010360)Merck KGaAIgG Open up in another window DNA/histoneVarious solid tumorsPhase IAE xenoN/DL19-TNF (Fibromun)PhilogenscFv Open up in another window EDB FibronectinMelanomaPhase I/IIAE+ syng w/melphalan or L19-IL2, VE650 g per injection in ILP with 10 mg/L limb quantity melphalan (up to at least one 1 mg well tolerated) br / 13 g/kg iv 1 weekly br / MTD not yet set up Open in another window Records: Philogen, Siena, Italy. Merck KGaA, Darmstadt, Germany. Antisoma/Novartis, Basel, Switzerland. Abbreviations: NH,.