Monovalent anti-properdin antibodies and antibody fragments
Inventors
Sheridan, Douglas L. • Tamburini, Paul P. • MACK, Taneisha Ann-Tanara • Voegtli, Walter C.
Assignees
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Publication Number
US-12497445-B2
Publication Date
2025-12-16
Expiration Date
Abstract
Described herein are isolated monovalent antibodies or antibody fragments thereof that bind human properdin. Such antibodies are useful in methods of treatment for diseases mediated by alternative complement pathway dysregulation.
Core Innovation
The invention relates to isolated monovalent anti-properdin antibodies and antibody fragments that specifically bind human properdin and selectively block alternative complement pathway activation. The provided embodiments include camelid single-domain formats, such as VHH, and antibody fragments comprising three CDRs with defined amino acid sequences (CDR-H1, CDR-H2, and CDR-H3). The antibodies or fragments destabilize C3/C5 convertase complexes and thereby reduce membrane attack complex (MAC) formation and alternative complement pathway-dependent hemolysis.
The invention further characterizes the disclosed anti-properdin antibodies by target/epitope and CDR/sequence embodiments, including specific CDR sequence listings. The disclosure also includes cross-species binding characterization indicating weak or no binding to mouse properdin. Constructs are described, including linked and bispecific formats, while maintaining a monovalent anti-properdin targeting element.
A stated problem addressed is alternative complement pathway dysregulation as implicated in disease. The disclosure includes treatment of atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria (PNH) by administering an effective amount of the isolated monovalent anti-properdin antibody or fragment thereof to a patient in need thereof. The disclosure also addresses minimizing aggregation-related toxicity associated with bivalent or multivalent antibodies.
Claims Coverage
Independent claim coverage is provided by a method claim directed to treating aHUS or PNH using an isolated monovalent antibody or fragment that binds human properdin and comprises three specified CDRs (H1, H2, and H3). Dependent claim coverage further narrows the indication and adds linked/second-antibody construction constraints and additional binding specificity.
Treating aHUS or PNH using an isolated monovalent anti-properdin antibody or fragment with defined CDR sequences
The method comprises administering an effective amount of an isolated monovalent antibody or fragment thereof that binds human properdin and comprises 3 CDRs comprising the amino acid sequences GRISSIIHMA (SEQ ID NO: 16) for CDR-H1, RVGTTVYADSVKG (SEQ ID NO: 12) for CDR-H2, and LQYEKHGGADY (SEQ ID NO: 17) for CDR-H3.
Treating aHUS
The method of treating aHUS comprises administering the effective amount of the isolated monovalent antibody or fragment thereof according to the constraints of the preceding claim.
Treating PNH
The method of treating PNH comprises administering the effective amount of the isolated monovalent antibody or fragment thereof according to the constraints of the preceding claim.
Linked second monovalent antibody using a poly-glycine linker containing a GGGGE sequence
The method further comprises linking an antibody (or fragment) to a second monovalent antibody (or fragment) using a poly-glycine linker that comprises a GGGGE (SEQ ID NO: 64) sequence.
Second monovalent antibody specifically binds albumin
The method further defines that the second monovalent antibody (or fragment thereof) specifically binds albumin.
N-terminal linking of the second monovalent antibody
The method further defines that the second monovalent antibody (or fragment thereof) is linked to the N-terminus of the antibody (or fragment thereof) that binds human properdin.
Overall, the claim set is anchored in administering an isolated monovalent anti-properdin antibody or fragment with three defined CDR sequences to treat aHUS or PNH, with dependent claim coverage adding linked bispecific/linked architecture constraints, including a poly-glycine linker comprising GGGGE, optional albumin-binding of a second monovalent antibody, and specification of attachment at the N-terminus.
Stated Advantages
Selectively blocks alternative complement pathway activation.
Destabilizes C3/C5 convertase complexes.
Reduces membrane attack complex (MAC) formation and alternative complement pathway-dependent hemolysis.
Minimizes aggregation-related toxicity associated with bivalent or multivalent antibodies.
Documented Applications
Treatment of atypical hemolytic uremic syndrome (aHUS) by administering an effective amount of the isolated monovalent antibody or fragment thereof that binds human properdin.
Treatment of paroxysmal nocturnal hemoglobinuria (PNH) by administering an effective amount of the isolated monovalent antibody or fragment thereof that binds human properdin.
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