Targeting and Clearance of AL Amyloidosis Deposits by NEOD001: A Novel Therapeutic Approach

The text discusses a prevalent systemic disorder known as light chain (AL) amyloidosis, which is marked by the buildup of misfolded light chain proteins in multiple organs, causing severe damage and impaired function. Presently, there are no approved treatments for AL amyloidosis, and existing methods do not address the root cause of organ malfunction. A phase 3 clinical trial is underway for a specific antibody, NEOD001, which targets light chain amyloid clumps and may facilitate the removal of AL deposits through phagocytosis.

The research involved the use of 2A4, a murine version of NEOD001, to prevent false detection of human immunoglobulin G in tissues. Various techniques were employed to assess 2A4's interaction with AL aggregates, including immunohistochemistry and biochemical methods. Examinations were conducted on 15 organs from 10 AL patients, utilizing both fresh and fixed tissue samples. The presence of amyloid was confirmed with Thioflavin T staining, and the antibody's binding was evaluated using surface plasmon resonance and a plate-based immunoassay.

The results showed that 2A4 selectively reacted with AL aggregates in patient samples across all organs tested, with no reaction in healthy controls. While the antibody's labeling was largely consistent with ThioT, some deposits were identified by 2A4 but not by ThioT, suggesting the presence of non-crystalline light chain deposits. The immunostaining was significantly reduced in fixed samples, even with brief fixation, and antigen-retrieval methods offered limited restoration. The immunoassay confirmed 2A4's binding to tissue extracts from AL patients but not from healthy subjects, and biochemical assays validated the antibody's specificity for aggregated over monomeric light chains. Furthermore, 2A4 was found to prompt macrophages to clear light chain aggregates in vitro.

The study concludes that 2A4, akin to NEOD001, selectively binds to amyloid and non-crystalline light chain aggregates in AL amyloidosis patients' organs and promotes their clearance by macrophage phagocytosis in vitro. This suggests that NEOD001 could be a promising therapeutic agent for directly addressing the root of organ dysfunction in AL amyloidosis.