Compositions for inhibiting MASP-2 dependent complement activation
Inventors
Dudler, Thomas • Gombotz, Wayne R. • Parent, James Brian • Tedford, Clark E. • Kavlie, Anita • Hagemann, Urs Beat • Reiersen, Herald • Kiprijanov, Sergej
Assignees
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Publication Number
US-11613589-B2
Publication Date
2023-03-28
Expiration Date
Abstract
The present invention relates to anti-MASP-2 inhibitory antibodies and compositions comprising such antibodies for use in inhibiting the adverse effects of MASP-2 dependent complement activation.
Core Innovation
The disclosure describes nucleic acids encoding human anti-MASP-2 antibodies or antigen-binding fragments, specifically heavy- and light-chain variable regions or complementarity determining regions. The heavy-chain variable region comprises SEQ ID NO:21, and the light-chain variable region comprises SEQ ID NO:25 or SEQ ID NO:27. The described antibodies bind human MASP-2 and inhibit lectin complement pathway activation while largely preserving classical and alternative pathway activity.
Candidate antibodies, including OMS646 and 17N16m_d17N9, demonstrate high-affinity binding to MASP-2 alongside concentration-dependent inhibition of C4 activation, C3 deposition, and membrane attack complex deposition. In vivo evaluations demonstrate lectin-pathway inhibition followed by recovery in monkeys, preferential binding to hMASP-2A over C1s, and improved survival following radiation exposure in mouse studies.
Claims Coverage
The claims provide three inventive features across three independent claims directed to nucleic acids encoding antibody components that bind human MASP-2 and a cell comprising those nucleic acids.
Nucleic acid encoding antibody complementarity determining regions
A nucleic acid encodes the complementarity determining regions of the heavy- and light-chain variable regions of an antibody, or antigen-binding fragment thereof, that binds human MASP-2, wherein the heavy-chain variable region comprises SEQ ID NO:21 and the light-chain variable region comprises SEQ ID NO:25 or SEQ ID NO:27.
Nucleic acid encoding antibody variable regions
A nucleic acid comprises a nucleotide sequence encoding the heavy- and light-chain variable regions of an antibody, or antigen-binding fragment thereof, that binds human MASP-2, wherein the heavy-chain variable region comprises SEQ ID NO:21 and the light-chain variable region comprises SEQ ID NO:25 or SEQ ID NO:27.
Cell comprising nucleic acids encoding antibody complementarity determining regions
A cell comprises a nucleic acid encoding the complementarity determining regions of the heavy-chain variable region comprising SEQ ID NO:21 and a nucleic acid encoding the complementarity determining regions of the light-chain variable region comprising SEQ ID NO:25 or SEQ ID NO:27 of an antibody or antigen-binding fragment that binds human MASP-2.
The independent claims cover nucleic acids encoding specified anti-MASP-2 antibody variable or complementarity determining regions and a host cell comprising those nucleic acids, with dependent claims addressing sequence alternatives, expression vectors, cells, and antibody production.
Stated Advantages
The described antibodies inhibit lectin-pathway complement activation, C4 activation, C3 deposition, and membrane attack complex deposition while largely preserving classical- and alternative-pathway activity.
The antibodies exhibit high-affinity binding to human MASP-2.
Evaluations report improved survival after radiation exposure compared to vehicle.
Documented Applications
The reported mouse survival results support application of the anti-MASP-2 antibodies to acute radiation syndrome.
Production of an antibody or antigen-binding fragment that binds human MASP-2 using a cell comprising the specified nucleic acids; [procedural detail omitted for safety].
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