Conformational neoepitope of misfolded human immunoglobulin light-chain amyloid fibrils

The target is a conformational neoepitope located within the first 18 amino acids of the N-terminal variable region of misfolded human immunoglobulin light chains (LCs) [1.2.1, 1.3.1]. This epitope is considered "cryptic" because it remains sequestered within the native, correctly folded structure of the light chain but becomes solvent-exposed upon the protein's misfolding and subsequent aggregation into insoluble amyloid fibrils [1.1.1, 1.2.4]. The presence of a conserved prolyl residue at position 8 is critical for the formation of the specific beta-turn structure that defines this neoepitope [1.3.1]. In patients with AL amyloidosis, these misfolded light chains and fibrils deposit in vital organs, most notably the heart and kidneys, where they exert proteotoxic effects and cause progressive organ dysfunction and failure [1.2.2, 1.2.3]. Therapeutic strategies targeting this neoepitope utilize monoclonal antibodies, such as anselamimab (CAEL-101), to selectively bind the misfolded species while sparing the normally folded, circulating native light chains [1.2.2, 1.4.1]. Upon binding, these antibodies neutralize toxic soluble aggregates and opsonize insoluble fibrils, thereby recruiting macrophages and neutrophils to facilitate the clearance of amyloid deposits through antibody-dependent cellular phagocytosis [1.2.2, 1.2.4]. This approach represents a novel mechanism of action aimed at directly reducing the existing amyloid burden and restoring organ function, complementing standard-of-care therapies that focus on eliminating the underlying plasma cell clone [1.1.2, 1.5.1].

Other names

11-1F4 epitopeCryptic light-chain epitopeN-terminal neoepitope of misfolded light chainsAL amyloid fibril neoepitope

Binding to misfolded light chains and fibrils to neutralize toxic aggregates and promote macrophage-mediated phagocytic clearance (opsonization) [1.2.2, 1.2.4].