SBIR Phase I: Novel Immuno-therapy for Specific Depletion of IgG4 Subtype of Autoantibodies

The broader/commercial impact of this Small Business Innovation Research (SBIR) Phase I project is the creation of a drug that allows for the specific depletion of a subclass of human antibodies (IgG4) that cause several different human diseases. Current treatments that deplete human antibodies do it without regard to antibody subclass, leading to a broadly suppressed immune system. In addition, there are over 10 IgG4-related diseases where the role of IgG4 is thought to be important but not the source of the disease. These include thrombotic thrombocytopenic purpura, pemphigus vulgaris and pemphigus foliaceus, anti-muscle-specific kinase myasthenia gravis, and primary membranous nephropathy. The proposed drug would allow the entire field to investigate the role of IgG4 in a specific disease. The mechanism by which the candidate drug proposes to deplete IgG4 could be leveraged to modify serum IgG4 with other similar drugs. Thus, the candidate drug would serve as a proof of concept for a mechanism that promises the drugmaker the ability to recombine endogenous serum IgG4 with additional drugs and modifications. These will have broad implications in a series of diseases ranging from IgG4s immunosuppressive role in oncology to anti-drug-antibodies that block the effect of many medicines.

The proposed project supports the creation of a drug that will recombine with endogenous pathogenic IgG4s leading to their rapid depletion. One Fab Arm Exchange Therapeutic (FAET) has already been identified that successfully recombines with hIgG4 in vitro, demonstrating proof-of-concept that this molecule is chemically competent for recombination. The final in vitro confirmation step will use Surface Plasmon Resonance to check the FcRn binding of the FAET molecule and the recombined hIgG4-FAET molecule. Due to mutations engineered within the FAET-Fc, it is expected that there will be no binding between FcRn and FAET, and minimal binding with the hIgG4-FAET molecule. Once confirmed the proper behavior of the molecule in vitro, the FAE efficacy will be assessed in vivo, with the anticipation that it will cause a decrease in the hIgG4 concentration. This basic mouse experiment, where the target hIgG4 will be injected along with the FAET molecule, can be used as a workhorse experiment to optimize different aspects of the FAET molecule and the mutations used to evince them.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Award Number: 2451302
Principal Investigator: Zhonghao Liu
Funds Obligated: $304,665
State: CA