Preclinical studies of PG70 LEAPS peptide vaccines for rheumatoid arthritis

CurrentlyFDA licensed pharmaceuticals used to treat rheumatoid arthritisRAfocus largely on alleviation of symptomseither through pain managementgeneral immunosuppressionor by antagonizing cytokines such as TNFDespite recent advances in biologic therapiesthese treatments do not address the underlying autoimmune conditionTo develop a peptide vaccine based therapy for RAwe used the human proteoglycanPGinduced arthritisPGIAand the closely related recombinant human PG Gdomain induced arthritisGIAmodels of RAtwo mouse models resembling the human disease in their pathologic and genetic featuresfemale preponderanceproduction of anti citrullinated protein antibodies and rheumatoid factorThe ligand epitope antigen presentation systemLEAPSis a peptide vaccine platform designed to modulate the immune response in an antigen specific mannerLEAPS peptides are composed of an immune cell binding ligandICBLconjugated to a disease related peptideautoepitopeOne of the LEAPS conjugates is CELwhich utilizes the DerG ICBL from the human MHC class IIchain that has T helper cellThpolarizing activitypotentially dampening Thor Thdriven autoimmune responses characteristic for RAIn the phase I SBIR studywe showed that CELa DerG LEAPS conjugate of the immunodominant epitopePGof the Gdomain of the PG moleculeeffectively treats arthritis in the PGIA and GIA models of RAWe hypothesized and then demonstrated that the CELLEAPS vaccine modulates the underlying immune responses that drive disease progression in PGIA and GIAEfficacy was demonstrated by suppressive effects of CELon arthritis severityhistopathology of peripheral jointsand cytokine responsesThe four Aims of the proposed phase II study areAimDetermine the in vitro T cell responses to CELthe antigen presenting function of CELtreated dendritic cellsDCsand whether the conjugate alone and or conjugate treated cells alter the differentiation of Thcells to distinct Th subsetsAimDemonstrate therapeutic efficacy of LEAPS activated DCs or T cellsor a mixture of bothfrom mice with GIA after ex vivo treatment of these cells with CELand adoptive transfer to immunodeficient miceAimExtend the CELbinding and activation studies to ratnon human primateNHPand human peripheral blood cellsAimMeet with FDA officialsreview the CELIND enabling program for in vivo immunogenicitytoxicity and safetyand conduct the relevant and agreed upon in vivo vaccine treatment studies in NHPPerform IND enabling studies using human cells and CELin a cytokine release assay as an independent assessment of a potential druginducedcytokine stormCompletion of these Aims will further elucidate the molecular basis for CELefficacy and lay the ground work for an IND submissionThe proposed studies will further our understanding of the therapeutic immune response elicited by LEAPS peptideand cell based vaccinesand initiate the steps towards human trials