Preclinical studies on targeted delivery of multiple IFNα2b to HLA-DR in diverse hematologic cancers

Abstract

The short circulating half-life and side effects of IFN␣ affect its dosing schedule and efficacy. Fusion of IFN␣ to a tumortargeting mAb (mAb-IFN␣) can enhance potency because of increased tumor localization and improved pharmacokinetics. We used the Dock-and-Lock method to generate C2-2b-2b, a mAb-IFN␣ comprising tetrameric IFN␣2b site-specifically linked to hL243 (humanized anti-HLA-DR). In vitro, C2-2b-2b inhibited various B-cell lymphoma leukemia and myeloma cell lines. In most cases, this immunocytokine was more effective than CD20-targeted mAb-IFN␣ or a mixture comprising the parental mAb and IFN␣. Our findings indicate that responsiveness depends on HLA-DR expression/density and sensitivity to IFN␣ and hL243. C2-2b-2b induced more potent and longer-lasting IFN␣ signaling compared with nontargeted IFN␣. Phosphorylation of STAT1 was more robust and persistent than that of STAT3, which may promote apoptosis.C2-2b-2b efficiently depleted lymphoma and myeloma cells from whole human blood but also exhibited some toxicity to B cells, monocytes, and dendritic cells. C2-2b-2b showed superior efficacy compared with nontargeting mAb-IFN␣, peginterferonalfa-2a, or a combination of hL243 and IFN␣, using human lymphoma and myeloma xenografts. These results suggest that C2-2b-2b should be useful in the treatment of various hematopoietic malignancies. (Blood. 2011;118(7):1877-1884)

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

“…Overall, these data suggest that higher doses of carfilzomib lead to greater levels of i20S inhibition, resulting in improved clinical responses in patients with MM. Although these data are derived from small numbers of patients and should be verified in larger, randomized trials, they do support previous findings of a dose‐response relationship seen with earlier phase II trials of single‐agent carfilzomib (Squifflet et al , 2011). …”

A new class of bispecific antibodies to redirect T cells for cancer immunotherapy

“…Since its inception in 2005, the DNL method, by combining DDD2-and AD2 modules derived from assorted classes of molecules that encompass IgG, [38][39][40][41] Fab, 34,42,43 cytokines, [44][45][46] polyethylene glycols, 47 and enfuvirtide, 48 has been used to produce more than 100 different complexes with potential applications for targeted therapies of malignant, autoimmune, and infectious diseases. The generation of a functional Okt3-scFv-AD2 and the demonstration of the in vitro and in vivo activities of various (X)-3s to kill target tumor cells via T cells, as described in this study, expands the applications of the DNL repertoire to now include scFv as a viable building block for future exploration.…”

Type I interferons in anticancer immunity

“…Such immuno therapeutics have already been shown to have antineo plastic effects in rodent tumour models 80 . For instance, C22b2b, an immunocytokine comprising tetrameric IFNα2b coupled to hL243 (a humanized monoclonal antibody that is specific for HLADR) is effective against human myeloma and lymphoma xenografts 81 . Similarly, IFNβ fused to cetuximab (a clinically approved EGFRtargeting monoclonal antibody) 82 limits the growth of mouse EGFRexpressing tumours that failed to respond to unmodified cetuximab 35 .…”