POS0094 ALPN-303, AN ENGINEERED DUAL BAFF/APRIL ANTAGONIST, POTENTLY INHIBITS PATHOGENIC LYMPHOCYTE SUBSETS AND FUNCTION IN B-CELL- AND ANTIBODY-RELATED PRECLINICAL MODELS

Abstract

BackgroundB-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are tumor necrosis factor (TNF) superfamily members that bind TACI (transmembrane activator and CAML interactor), BCMA (B-cell maturation antigen), and/or BAFF-R on B cells and together support B cell development, differentiation, and survival. ALPN-303 is an Fc fusion protein of a human TACI variant TNFR domain engineered by directed evolution1,2. It mediates significantly improved combined BAFF and APRIL inhibition in vitro and enhanced pharmacokinetic and immunomodulatory properties in preclinical studies, as compared to wild-type (WT) TACI-Fc molecules. B-cell targeting therapies like the WT TACI-Fc fusions atacicept and telitacicept have demonstrated promising clinical potential in B cell-related diseases like systemic lupus erythematosus (SLE). ALPN-303, with enhanced inhibitory activity against BAFF and APRIL, has previously been shown to demonstrate promising efficacy in an (NZB/NZW)F1 mouse model of lupus, and may therefore further improve clinical outcomes in such diseases.ObjectivesTo further characterize the comparative activity of ALPN-303 versus an Fc matched control, a WT TACI-Fc comparator (telitacicept), and/or a B cell-depleting therapy (anti-mouse CD20 [anti-mCD20] monoclonal antibody [mAb]), in antibody-related preclinical models.MethodsThe functional activity of ALPN-303, as compared to telitacicept or a depleting anti-mCD20 mAb, was evaluated in a sheep red blood cell (SRBC) immunization mouse model. Mice immunized intraperitoneally with SRBC on Study Day 0 were administered 200 µg ALPN-303 or a molar-matched amount (240 µg) of telitacicept on Days 1 and 6 or were treated with 200 µg anti-mCD20 (rat IgG2b) on Day 1. At study termination on Day 15, serum was collected to measure levels of test article and anti-SRBC immunoglobulin (Ig) titers, and spleens and bone marrow (BM) were collected for immunophenotyping by flow cytometry. A study in the inducible bm12 mouse model of lupus was also conducted, with mice treated twice weekly with 200 µg ALPN-303 or a molar-matched dose of Fc control, starting on Day 5 after splenocyte transfer and continuing through Week 13.ResultsALPN-303 administration rapidly and potently reduced BM plasma cells, splenic germinal center B cells, follicular T helper cells, and plasmablasts in SRBC-immunized mice, often significantly more so than telitacicept and/or anti-mCD20 mAb. ALPN-303 also significantly reduced serum titers of anti-SRBC IgM, IgG1, IgG2a, and IgG2b as compared to all other treatment groups. In the bm12 model, ALPN-303 treatment significantly impacted the same key lymphocyte subsets affected in the SRBC model, and significantly reduced circulating anti-dsDNA antibodies (Figure 1) and total IgA, IgM, IgG1, IgG2b, and IgG3, and inhibited renal IgG deposits (Figure 1).Figure 1.ALPN-303 treatment significantly reduces serum autoantibody titers and renal immune complex deposition in the inducible bm12 mouse model of lupus. *p<0.05, **p<0.01, ****p<0.0001 by the Kruskal-Wallis test.ConclusionALPN-303 is an engineered, potent BAFF/APRIL antagonist that continues to consistently demonstrate encouraging immunomodulatory activity and efficacy in vitro and in vivo, as further demonstrated in the SRBC immunization and bm12 lupus models, with superiority to WT TACI-Fc and anti-CD20 comparators. ALPN-303 may thus be an attractive development candidate for the treatment of multiple autoimmune and inflammatory diseases, particularly B cell- and/or autoantibody-related diseases such as SLE, Sjögren’s syndrome, and other connective tissue diseases. A Phase 1 study of ALPN-303 in adult healthy volunteers (NCT05034484) is ongoing.