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Publication Number
US-11903994-B2
Publication Date
2024-02-20
Expiration Date
Abstract
In some aspects, the present invention provides cell-reactive compstatin analogs and compositions comprising cell-reactive compstatin analogs. In some aspects, the invention further provides methods of using cell-reactive compstatin analogs, e.g., treat a complement-mediated disorder, e.g., to inhibit complement-mediated damage to a cell, tissue, or organ. In some aspects, the invention provides long-acting compstatin analogs and compositions comprising long-acting compstatin analogs. In some aspects, the invention further provides methods of using long-acting compstatin analogs, e.g., to treat a complement-mediated disorder, e.g., to inhibit complement-mediated damage to a cell, tissue, or organ. In some aspects, the invention provides targeted compstatin analogs and compositions comprising targeted compstatin analogs. In some aspects, the invention further provides methods of using targeted compstatin analogs, e.g., to treat a complement-mediated disorder, e.g., to inhibit complement-mediated damage to a cell, tissue, or organ.
Core Innovation
The invention relates to complement-inhibiting compstatin analog drug concepts, including long-acting compstatin analogs (LACA) and their use in complement-mediated disorders. It addresses treating complement-mediated eye disorders by administering a LACA in a manner intended to prolong activity by reducing clearance and extending the duration of complement inhibition.
A key concept is that LACA embodiments include a clearance reducing moiety such as PEG to support extended dosing intervals. The disclosed LACA designs also include compstatin analog moieties that are cyclic peptide moieties, with specific structural linkages to the PEG through defined spacers and carbamate linkages.
The disclosed embodiments include cell-reactive compstatin analogs and targeted compstatin analogs, including tethering through maleimide and N-hydroxysuccinimide (NHS) ester linkers for cell association. The document further discusses branched PEG architectures, additional linker chemistries, and alternative clearance-reducing polymers such as polyoxazoline.
Claims Coverage
The independent claim coverage centers on intravitreal treatment of geographic atrophy with a structurally defined long-acting compstatin analog administered monthly or every other month. The inventive features include the dosing regimen and a PEG-based LACA structure with two cyclic compstatin analog moieties, an AEEAc spacer, and carbamate linkages.
Intravitreal monthly or every-other-month LACA dosing for geographic atrophy
A method of treating a subject in need of treatment for a complement-mediated eye disorder comprising intravitreally administering about 15 mg of a long-acting compstatin analog (LACA) monthly or every other month to the eye of the subject, wherein the complement-mediated eye disorder is geographic atrophy.
PEG-CRM long-acting architecture with two compstatin analog moieties
The LACA comprises a PEG having an average molecular weight of 40 kD attached to two compstatin analog moieties.
Cyclic compstatin analog moieties with lysine extension and AEEAc spacer
Each compstatin analog moiety comprises a cyclic peptide having the amino acid sequence as set forth in SEQ ID NO: 28 extended by a lysine residue at the C-terminus, wherein the lysine residue is separated from the cyclic portion of the peptide by an 8-amino-3,6-dioxaoctanoic acid (AEEAc) spacer.
Carbamate PEG-to-lysine side-chain linkage at both PEG ends
Each end of the PEG is linked to the amino group of the side chain of the lysine residue of one of the compstatin analog moieties by way of a carbamate.
The claim coverage centers on intravitreal monthly or every-other-month treatment for geographic atrophy using a 40 kD PEG-linked LACA with two cyclic compstatin analog moieties, where the PEG termini are connected through AEEAc-spaced lysine side chains by carbamate linkages.
Stated Advantages
Reduction of complement activation and C3 deposition.
Protection of PNH patient RBCs from complement-mediated lysis.
Sustained therapeutic effect associated with exposure and durability, including terminal half-life and serum levels.
Prolonged activity of complement inhibition via long-acting compstatin analogs using clearance reducing moieties such as PEG.
Documented Applications
Treating a complement-mediated eye disorder, geographic atrophy, by intravitreal administration of a long-acting compstatin analog monthly or every other month.
Evaluating compstatin analogs for complement inhibition in a modified Ham’s test, including inhibition of C3 deposition and protection of PNH patient RBCs from complement-mediated lysis.
Treatment of a complement-mediated eye disorder, specifically geographic atrophy, by intravitreal administration of a long-acting compstatin analog (LACA).
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