Research thoughts by:

Gareth Morgan

The role of antibody stability in plasma cell malignancies

9/12/2021

Research in my laboratory focus on the pathologic roles of antibodies secreted by B cell cancers. Plasma cells are long-lived, non-proliferating B cells in the bone marrow that secrete large amounts of a single antibody, providing long-term immunity against disease. Antibody production requires a large fraction of the cells’ resources, and plasma cells are highly specialized. Errors in B cell development can lead to uncontrolled proliferation of clonal plasma cells, resulting in a spectrum of diseases including multiple myeloma, an incurable cancer that afflicts an estimated 140,000 Americans. Clonal plasma cells continue to secrete their specific antibody, which can be detected in blood as an “M-protein”.

 

Antibody fragments can cause symptoms throughout the body, independently of the cancerous plasma cells. One serious manifestation is amyloidosis, where antibody light chain proteins misfold and aggregate in multiple tissues. Amyloidosis most often occurs in the context of a small, slow-growing population of clonal plasma cells, which would otherwise be considered a precursor to myeloma, but is serious and eventually fatal if untreated. Only a fraction of individuals with plasma cell disorders develop amyloidosis, apparently due to the properties of each patient’s unique antibody protein.

 

My work has focused on identifying the biochemical characteristics of antibody light chains that lead to their aggregation and cause amyloidosis. A key property is the stability of the light chain, which is its ability to maintain its correctly folded structure. Unstable light chains are more prone to unfolding and forming amyloid, so we reasoned that a drug which can stabilize light chains could prevent amyloidosis. We have been able to design and synthesize molecules that stabilize light chains and are actively developing these molecules as potential drug candidates.

 

From the perspective of a cancer cell, however, unstable proteins are a burden that require effort to synthesize and secrete. A cell whose antibody is unstable needs to expend resources on quality control systems that could otherwise be used to grow. Synthesis of unstable proteins activates the unfolded protein response in cells, a signaling pathway that upregulates molecular chaperones and other factors that help proteins to fold. Overactivation of this response eventually leads to cell death by apoptosis. B cells upregulate some unfolded protein response pathways as they mature into plasma cells, but maintain this state indefinitely without triggering apoptosis. Therefore, we hypothesize that there is a tradeoff between antibody production and proliferation in myeloma cells that could be exploited for therapy. This balance could explain why plasma cells from patients with amyloidosis grow slowly. One class of frontline drugs for myeloma is proteasome inhibitors, which prevent clearance of damaged or misfolded proteins. There is some evidence that plasma cells with unstable antibodies are more susceptible to proteasome inhibitors than other cells, but what role this plays in response and resistance is unclear.

 

We aim to combine protein stability measurements and gene expression profiling to clarify this relationship between the antibody that a cancerous plasma cell makes, the stress that the antibody induces, and the resources that the cell has to divert from growth. Identifying processes and signaling pathways that allow plasma cells to survive could identify new targets for drugs. Our access to plasma cells from individuals with amyloidosis is critical to this project, since we know that these cells are secreting unstable, aggregation-prone proteins. Comparing plasma cells from amyloidosis to those from myeloma will highlight differences in their biology. This work is at an early stage, so the funding from the Karin Grunebaum Cancer Research Foundation will enable us to complete our first experiments and establish the systems that we need to move forwards.

 

Beyond myeloma, understanding how cancer cells continue to perform their original functions, and when they are able to escape from the original limitations of their biology is important for many cancers. Protein folding and quality control are fundamental processes, underlying many core cellular systems. Cancer cells must maintain their proteins in folded, functional states even as they accumulate damaging mutations, and the protein quality control systems are critical to these processes. In theory, cancer cells should be more vulnerable to protein folding stress than healthy cells but inhibiting these pathways for therapy has been difficult. Learning how to specifically target the systems involved could lead to new therapies and benefit many patients.