title: Lipid- and polyion complex-based micelles as agonist platforms for TNFR superfamily receptors.
abstract: Receptor clustering is important for signaling among the therapeutically relevant TNFR superfamily of receptors. In nature, this clustering is driven by trimeric ligands often presented in large numbers as cell surface proteins. Molecules capable of driving similar levels of clustering could make good agonists and hold therapeutic value. However, recapitulating such extensive clustering using typical biotherapeutic formats, such as antibodies, is difficult. Consequently, generating effective agonists of TNFR superfamily receptors is challenging. Toward addressing this challenge we have used lipid- and polyion complex-based micelles as platforms for presenting receptor-binding biologics in a multivalent format that facilitates receptor clustering and imparts strong agonist activity. We show that receptor-binding scFvs or small antibody mimetics that have no agonist activity on their own can be transformed into potent agonists through multivalent presentation on a micelle surface and that the activity of already active multivalent agonists can be enhanced. Using this strategy, we generated potent agonists against two different TNFR superfamily receptors and mouse tumor model studies demonstrate that these micellar agonists have therapeutic efficacy in vivo. Due to its ease of implementation and applicability independent of agonist molecular format, we anticipate that this strategy could be useful for developing agonists to a variety of receptors that rely on clustering to signal.
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, MD 20878, USA. Electronic address: gilbrethr@medimmune.com.
authors.forename: Ryan N
authors.initials: RN
authors.lastname: Gilbreth
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Shabazz
authors.initials: S
authors.lastname: Novarra
authors.affiliation: Department of Oncology Research, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Wetzel
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Stelios
authors.initials: S
authors.lastname: Florinas
authors.affiliation: Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors.forename: Horacio
authors.initials: H
authors.lastname: Cabral
authors.affiliation: Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: Department of Oncology Research, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rios-Doria
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Christie
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Baca
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D019169:Jurkat Cells; D008301:Maleimides / Q000737:chemistry*; D051379:Mice; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D010714:Phosphatidylethanolamines / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011485:Protein Binding; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists*; D057127:Single-Chain Antibodies / Q000008:administration & dosage* / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D008301:Maleimides; D008823:Micelles; D010714:Phosphatidylethanolamines; D018124:Receptors, Tumor Necrosis Factor; D057127:Single-Chain Antibodies; C107570:polyethylene glycol-distearoylphosphatidylethanolamine; C043592:maleimide; D011092:Polyethylene Glycols
keywords: Fas; Multivalent; Nanoparticles; Receptor clustering; TRAILR2; Tn3