Factor H potentiating antibodies and uses thereof
Inventors
Kuijpers, Taco Willem • WOUTERS, Diana • BROUWER, Maria Clara • POUW, Richard Benjamin
Assignees
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Publication Number
US-10112993-B2
Publication Date
2018-10-30
Expiration Date
Abstract
The invention relates to isolated, synthetic or recombinant antibodies and fragments thereof specific for factor H. The invention further relates to the use of such antibodies and fragments for inhibiting complement activation and treatment of disorders associated with complement activation.
Core Innovation
The invention relates to factor H (FH) potentiating monoclonal antibodies and fragments that specifically bind complement control protein domain 18 (CCP18) of FH. The antibodies or fragments include defined heavy chain CDR1, CDR2 and CDR3 sequences and/or defined light chain CDR1, CDR2 and CDR3 sequences for CCP18 binding, including embodiments using Fab and other antibody fragments.
The problem addressed is alternative complement activation in disorders linked to alternative pathway complement activation, for example atypical hemolytic uremic syndrome (aHUS). The disclosed antibodies and fragments enhance FH activity, thereby inhibiting alternative complement activation at the level of C3, including strengthening FH inhibition at C3 convertase and reducing downstream C3-related activation.
In vitro findings described include that anti-FH.07 blocks SRBC hemolysis induced by FH-blocking antibodies or aHUS sera. The disclosure also reports inhibition of C3 deposition on zymosan and LPS and restoration of FH protective function across multiple aHUS patient sera, with potentiation by Fab’ fragments supporting the conclusion that the effect is not due to FH crosslinking.
Claims Coverage
The independent claim is directed to an isolated synthetic or recombinant antibody or fragment that specifically binds FH CCP18 using defined CDR sequences. The independent coverage includes four main inventive aspects: (i) CCP18-binding antibodies or fragments defined by specific CDR sequences, (ii) CCP18-binding antibodies or fragments with alternative complement inhibition effects, (iii) sequence-identity constraints on heavy or light chains, and (iv) therapeutic treatment of disorders linked to alternative pathway complement activation.
Cdr-defined ccp18-binding antibody or fragment
An isolated, synthetic or recombinant antibody or fragment thereof that specifically binds complement control protein domain 18 (CCP18) of factor H (FH), the antibody or fragment comprising a heavy chain CDR1 having the sequence of SEQ ID NO:5, a heavy chain CDR2 having the sequence of SEQ ID NO:6 and a heavy chain CDR3 sequence having the sequence of SEQ ID NO:7, or a light chain CDR1 sequence having the sequence of SEQ ID NO:1, a light chain CDR2 sequence having the sequence of SEQ ID NO:2 and a light chain CDR3 having the sequence of SEQ ID NO:3.
Alternative complement inhibition by ccp18-binding antibody or fragment
An antibody or its fragment that inhibits alternative complement activation by blocking hemolytic activity, inhibiting C3 deposition on an individual’s cells, and/or increasing FH binding to C3b, iC3b, and/or C3d.
Sequence-identity constrained heavy or light chain variants
An antibody or fragment wherein the antibody comprises either a heavy-chain sequence with at least 80% identity to SEQ ID NO:8 or a light-chain sequence with at least 80% identity to the sequence of SEQ ID NO:4.
Treatment of disorders linked to alternative pathway complement activation
A method for treating a disorder selected from atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), age-related macular degeneration (AMD), and membranoproliferative glomerulonephritis (MPGN).
Overall, the claim coverage is anchored in CCP18-specific antibodies or fragments defined by particular heavy or light CDR sequences, with additional coverage for inhibitory function on alternative complement activation, including hemolytic activity and C3 deposition, and with quantitative sequence-identity constraints and specified therapeutic indications.
Stated Advantages
Potentiation of FH activity to inhibit alternative complement activation at the level of C3.
Strengthening FH inhibition at C3 convertase and inhibiting downstream alternative complement activation.
Blocks SRBC hemolysis induced by FH-blocking antibodies or aHUS sera.
Inhibits C3 deposition on zymosan and LPS.
Restores FH protective function across multiple aHUS patient sera.
Potentiation by Fab’ fragments indicates the effect is not due to FH crosslinking.
Documented Applications
In vitro inhibition of SRBC hemolysis induced by FH-blocking antibodies or aHUS sera.
Inhibition of C3 deposition on zymosan and LPS.
Restoring FH protective function across multiple aHUS patient sera.
Treatment of atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), age-related macular degeneration (AMD), and membranoproliferative glomerulonephritis (MPGN).
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