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Complement inhibitors (fB and MASP-2) proved to be a very effective approach for complement mediated nephritis. However, due to the complexity of the complement system, including multiple pathways (CP, AP and LP) and potential cross-talk between AP and LP, blocking single complement pathway alone may not be sufficient to control the progression of nephritis (IgAN, lupusN and etc).
Thus, a next-generation complement inhibitor emerges as C5 antibody fused with another functional part of complement inhibition activity, providing a potentially broader clinical indication (nephritis, neuromyelitis and etc) with better efficacy and controlled risk.
The sequence of Eculizumab, Ravulizumab, Crovalimab, Pozelimab, Narsoplimab, were obtained from INN. POT-4 (also called APL-1) was purchased from MedChemExpress.
LP-005 was generated from hybridoma, fused with sponsor's proprietary inhibitor (inCibitorTM). Surrogate antibody fusion protein (LP-005C) .
Ab-fH was generated by fusing fH 1-5 to the C terminal of anti-C5 antibody.
All antibodies were expressed by HEK293 cells.
For CP and AP inhibition assay, sheep or rabbit erythrocytes was used with 5-10% NHS (normal human serum).
For LP inhibition assay, WIESLAB® MBL pathway kit was used.
C3b deposition on rabbit erythrocytes was detected by flow cytometry, after AP activation.
Single i.v. dose of Surrogate antibody fusion protein (LP-005C) and Ab-fH fusion protein was administrated in Monkey PK/PD study, PK and PD (hemolysis) assay was conducted.
In the present study, LP-005 shows the most potent inhibition in CP, AP and LP compared to Eculizumab, Ravulizumab, Crovalimab, Pozelimab and Narsoplimab (figure).
In addition, it also has the most efficient inhibition in C3b assay compared to Antibody-fH fusion and POT-4 (APL-1) (figure).
The monkey PK/PD study indicates that when fusing to the same C5 antibody, Longbio’s unique inhibitor (inCibitorTM) shows a better PK/PD profile compared to the natural fH 1-5 fragment.
In summary, LP-005 is a novel bifunctional anti-C5 monoclonal antibody fusion protein, with highest bioactivity in CP, AP, LP.
LP-005 is also engineered to change it surface charge (PI) and FcRn binding, which together has the potential to be a best-in-class drug candidate with improved pharmacokinetic properties and strongest in-vitro and in-vivo bioactivity.