title: Polymeric microparticles for sustained and local delivery of antiCD40 and antiCTLA-4 in immunotherapy of cancer.
abstract: This study investigated the feasibility of the use of polymeric microparticles for sustained and local delivery of immunomodulatory antibodies in immunotherapy of cancer. Local delivery of potent immunomodulatory antibodies avoids unwanted systemic side effects while retaining their anti-tumor effects. Microparticles based on poly(lactic-co-hydroxymethyl-glycolic acid) (pLHMGA) and loaded with two distinct types of immunomodulatory antibodies (CTLA-4 antibody blocking inhibitory receptors on T cells or CD40 agonistic antibody stimulating dendritic cells) were prepared by double emulsion solvent evaporation technique. The obtained particles had a diameter of 12-15 μm to avoid engulfment by phagocytes and were slightly porous as shown by SEM analysis. The loading efficiency of the antibodies in the microparticles was >85%. The in vitro release profile of antiCD40 and antiCTLA-4 from microparticles showed a burst release of about 20% followed by a sustained release of the content up to 80% of the loading in around 30 days. The therapeutic efficacy of the microparticulate formulations was studied in colon carcinoma tumor model (MC-38). Mice bearing subcutaneous MC-38 tumors were treated with the same dose of immunomodulatory antibodies formulated either in incomplete Freund's adjuvant (IFA) or in microparticles. The antibody-loaded microparticles showed comparable therapeutic efficacy to the IFA formulation with no local adverse effects. The biodegradable microparticles were fully resorbed in vivo and no remnants of inflammatory depots as observed with IFA were present in the cured mice. Moreover the microparticles exhibited lower antibody serum levels in comparison with IFA formulations which lowers the probability of systemic adverse effects. In conclusion, pLHMGA microparticles are excellent delivery systems in providing long-lasting and non-toxic antibody therapy for immunotherapy of cancer.
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Sima
authors.initials: S
authors.lastname: Rahimian
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marieke F
authors.initials: MF
authors.lastname: Fransen
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Kleinovink
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Maryam
authors.initials: M
authors.lastname: Amidi
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: F.A.Ossendorp@lumc.com.
authors.forename: Ferry
authors.initials: F
authors.lastname: Ossendorp
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. Electronic address: W.E.Hennink@uu.nl.
authors.forename: Wim E
authors.initials: WE
authors.lastname: Hennink
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000276:immunology*; D002214:Capsules / Q000008:administration & dosage / Q000138:chemical synthesis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000138:chemical synthesis*; D004058:Diffusion; D007155:Immunologic Factors / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; D002214:Capsules; D003692:Delayed-Action Preparations; D007155:Immunologic Factors
keywords: AntiCD40; CTLA4-blocking antibody; Cancer immunotherapy; Immunomodulatory antibody; Incomplete Freund's adjuvant (IFA); Local delivery; Sustained release; pLHMGA