title: A new platform for constructing antibody-cytokine fusion proteins (immunocytokines) with improved biological properties and adaptable cytokine activity.
abstract: A novel method for constructing immunocytokines has been developed that utilizes fusion of cytokines to the C-terminus of the Ig light chain, rather than fusing to the heavy chain. Such molecules are expressed well in transfected cells, are very stable in normal buffers and have biological properties that are superior to immunocytokines made by fusion to the heavy chain. These properties include longer circulating half-life, increased uptake following subcutaneous dosing and similar or improved antibody effector activities of antibody-dependent cytotoxic activity and complement-dependent cytotoxicity, respectively. Furthermore, the sequestering effect of this fusion junction allows one to adjust intermediate affinity (βγ) interleukin 2 receptor (IL2R) binding and activation by shortening the N-terminus of IL2 at the fusion point. This appears to limit access of the critical contact residue Asp20 of IL2 to the β-chain of βγ IL2R, while maintaining binding and activation of high-affinity (αβγ) IL2R-expressing cells. Several immunocytokine forms with varying degrees of IL2R specificity have been constructed, and some appear to regain their activity for the βγ IL2R when bound to antigen-coated beads. Such molecules may have reduced toxicity in the circulation and enhanced anti-tumor activity.
authors.affiliation: Provenance Biopharmaceuticals Corp., 70 Bedford Road, Carlisle, MA 01741, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Gillies
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000276:immunology*; D002460:Cell Line; D016207:Cytokines / Q000737:chemistry / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006031:Glycosylation; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D015202:Protein Engineering / Q000379:methods*; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology* / Q000493:pharmacokinetics; D013379:Substrate Specificity
chemical_list: D000906:Antibodies; D016207:Cytokines; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins
keywords: immunocytokine; interleukin 2; receptor specificity