Abstract
Immunoglobulin light chain amyloidosis (AL amyloidosis) is a rare systemic disease characterized by monoclonal light chains (LCs) depositing in tissue as insoluble fibrils, causing irreversible tissue damage. The mechanisms involved in aggregation and deposition of LCs are not fully understood, but CD138/38 plasma cells (PCs) are undoubtedly involved in monoclonal LC production.CD38 is a pleiotropic molecule detectable on the surface of PCs and maintained during the neoplastic transformation in multiple myeloma (MM). CD38 is expressed on T, B and NK cell populations as well, though at a lower cell surface density. CD38 is an ideal target in the management of PC dyscrasia, including AL amyloidosis, and indeed anti-CD38 monoclonal antibodies (MoAbs) have promising therapeutic potential. Anti-CD38 MoAbs act both as PC-depleting agents and as modulators of the balance of the immune cells. These aspects, together with their interaction with Fc receptors (FcRs) and neonatal FcRs, are specifically addressed in this paper. Moreover, the initiallyavailable experiences with the anti-CD38 MoAb DARA in AL amyloidosis are reviewed.
Highlights
Systemic amyloidosis is characterized by abnormal production and deposition in the extracellular space of misfolded proteins, resulting in a heterogeneous spectrum of clinical conditions [1]
CD38 could represent an effective molecule to be targeted by therapeutic antibodies in the management of AL amyloidosis, a pathologic condition characterized by high expression of this molecule at the cell surface level [19]
The understanding of the pathogenesis of tissue damage in AL amyloidosis has remarkably improved in recent years
Summary
Systemic amyloidosis is characterized by abnormal production and deposition in the extracellular space of misfolded proteins, resulting in a heterogeneous spectrum of clinical conditions [1]. Multiple roles have been described for CD38, as a receptor, adhesion molecule and ectoenzyme [18] Due to these characteristics, CD38 could represent an effective molecule to be targeted by therapeutic antibodies in the management of AL amyloidosis, a pathologic condition characterized by high expression of this molecule at the cell surface level [19]. DARA is able to reduce the expression of CD38 on the cell surface by trogocytosis This effect is based on a switch of the CD38-antiCD38 MoAb complex between the abnormal PCs, monocytes, and neutrophils. From being involved in the activation of effector cells and direct cytotoxicity, are able to upregulate CD38 These mechanisms represent an indication for combining MOR202 with IMiD compounds. Insights of efficacy and safety in AL amyloidosis are presently limited to DARA
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