HL161 (Anti-FcRn mAb for Autoimmune Diseases)
HanAll is currently developing fully human monoclonal antibodies targeting the Fc Neonatal Receptor (FcRn) for the treatment of autoimmune diseases caused by IgG autoantibodies and immune complex (IC) mediated glomerular diseases
FcRn mainly functions to prolong the half-life of IgG in serum via protecting IgG from catabolism, augment both humoral and cellular immunity via facilitating the presentation or cross-presentation of immune-complexed antigens, and clear IgG on the glomerular basement membrane. While these properties contribute to the enhancement of protective immunity, they also bring about deleterious effects in the spectrum of autoimmune diseases by promoting the accumulation of pathogenic IgG autoantibody, aggravating autoimmunity by boosting humoral and cellular immunity, and increasing immune complex deposition on the glomerular basement membrane and inducing inflammatory responses.
FcRn protects IgG from lysosomal degradation, thus prolonging the half-life of IgG in the serum
Nat Rev Immunol, 2007, 7:715-725, Derry C. Roopenian&ShreeramAkilesh
Various autoimmune diseases involve autoantibodies with IgG isotypes, as well as both cellular and humoral immune responses to auto-antigens in its pathogenesis. Moreover, autoimmune diseases such as Pemphigus Vulgaris (PV), NeuromyelitisOptica (NMO), Myasthenia Gravis (MG), Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Lupus Nephritis (LN), and Membranous Nephropathy (MN), among others, have all been associated with the presence of circulating autoantibodies against specific auto-antigens. When autoantibodies bind to antigens, these autoantibodies form immune complexes that are recognized as pathogenic and attacked by the body's immune system. Although the pathogenesis of autoimmune diseases has not been fully elucidated yet, the neonatal Fc receptor (FcRn) has come to the forefront as a potential therapeutic target for various autoimmune diseases.
HanAll BioPharma Co., Ltd has been developing HL161, a novel anti-FcRn antibody through two parallel methods consisting of a phage library screening and transgenic animal platform producing fully human monoclonal antibodies. HL161 possesses a triple mode of action by blocking FcRn through: 1) the increase the catabolism of pathogenic autoantibodies in circulation, 2) suppressing the immune complex-mediated humoral and cellular immunity and 3) by decreasing the glomerular immune complex deposition and inflammatory responses, thereby exerting therapeutic effects on various autoimmune diseases.
Three optimized candidate molecules have been obtained that demonstrate a high binding affinity (0.1~1nM) on hFcRn at both pH 6.0 and 7.4 and they efficiently block the interaction between hFcRn and hIgG at pH 6.0. According to PK/PD studies in FcRn-humanized mice, HL161 molecules presented more than an 8 fold increase in hIgG catabolism, which is almost as effective as the genetic ablation of FcRn, and demonstrated a good dose-proportional response at 5, 10, 20 mg/kg in mice. Further PK/PD studies in non-human primate are ongoing.
In comparison with other therapeutic options, HanAll believes that HL161 antibodies would be a promising, new alternative with potential advantages including i) significant therapeutic effect, ii) smaller doses compared to IVIG, iii) cost-effective compared to IVIG and plasmapheresis, iv) reduced adverse drug events (i.e. opportunistic infection) due to selectivity against IgG, unlike B-cell inhibitors.
HanAll is also planning to include new research area of inhibition of protein-protein interaction via small molecules and peptidomimetics. HanAll is seeking a partner to accelerate the global development of HL161 through licensing-out, option agreement and research collaboration.