Blockade of Human CD21 with a Humanized Blocking Antibody

Systemic lupus erythematosus (SLE) is a devastating autoimmune disease characterized by a person’s immune cells mistakenly targeting their own cells as foreign. Autoantibodies, produced by an immune cell called B cells, bind and form complexes with a person’s own cellular contents, or antigens. These autoantibody-antigen complexes can deposit in and cause damage to various tissues, including the kidney. Therapies that block the source of harmful autoantibodies and other cell types critical to this process are needed. Dr. Carroll has developed a therapeutic antibody that targets CD21, a molecule involved in the activation of B cells. This monoclonal antibody blocks B cell activation without depleting the B cells. He will now assess the therapeutic potential of this CD21 antibody (anti-CD21) in a mouse model of lupus and cells from people with SLE.

After encountering their specific target, activated B cells can become either antibody-secreting cells (ASCs) or memory B cells (MBCs). ASCs produce thousands of antibodies to provide immediate defense against the current infection. MBCs “remember” the antigen, enabling a faster, stronger immune response upon seeing the same invader even years later. In lupus, ABCs and MBCs can both be self-reactive. Dr. Carroll will assess whether blocking CD21 with the monoclonal antibody reduces self-reactive ASCs and MBCs in a mouse model of lupus.  Lastly, as lupus varies widely from person to person, Dr. Carroll will assess the effects of anti-CD21 on B cell activation in cells from people with SLE with a wide range of disease severity, clinical features, and treatment history.

What this study means for people with lupus

The production of autoantibodies is critical for the development and progression of lupus. Dr. Carroll’s evaluation of a new therapeutic approach that blocks B cell activation without depleting B cells themselves could open the door to a new, targeted treatment approach for people with lupus without leaving them at risk of infections.

Complement receptor CD21 (Cr2) forms a co-receptor with CD19 and CD81 on mature B cells and follicular dendritic cells which binds C3d coupled immune complexes (IC) to lower the threshold for activation of naïve B cells. On FDC expression of CD21 provides a major receptor for internalization of C3-IC into cycling endosomal compartment for long term retention. Moreover, uptake of nucleic acid containing IC (DAMPS) via CD21 on FDC can lead to activation of NF-kb and triggering of Type I interferon. Thus, CD21 serves a dual role as a B cell co-receptor and as a regulator of antigen (both foreign and self) uptake and retention as well as a potential source of Type I interferon. Deficiency in CD21 in mice results impaired primary and secondary immune responses against foreign antigens. Although rare, humans bearing loss of function mutation in CD21 have hypogammaglobulinemia, reduced isotype switching and memory B cells and increased susceptibility to infection. Given the central role of CD21 in B cell responses, Pfizer’s CTI program in partnership with LRA and my institution BCH, established a program to develop a neutralizing monoclonal antibody (mAb) specific for CD21 binding of C3d ligand as a potential therapeutic in lupus. Over the 5 year program in which I was PI of a joint project, a blocking antibody was developed with a high affinity (sub-nanomolar) for the human and cynomolgus CD21 receptor. The monoclonal was efficient in significant blockade of C3d-IC on human B cells and blockade of primary B cell activation of the serine-threonine kinase akt (Protein kinase B). However, the program was terminated in Feb 2021 due to Pfizer’s commitment to development of a COVID-19 vaccine. Pfizer and BCH are actively looking for a licensee to develop the antibody for clinical trials. My goal is to determine whether the antibody has efficacy in a preclinical lupus model. To this end, we have crossed the human CD21 BAC transgenic line with a mouse CD21 deficient strain to generate mice in which the B cells and FDC express a functional huCD21 receptor (referred to here as huCD21 strain). Likewise, we find that the huCD21 B cells behave similar to WT in development of autoreactive B cells.

The overall objective is to characterize lupus B cells following treatment with a mAb antibody to human CD21 receptor in a novel murine lupus model and in primary lupus patient B cell culture system. Two specific aims are proposed: Aim 1 will test hypothesis that blockade of huCD21receptor on B cells impairs formation of autoreactive extrafollicular (EF) antibody secreting cells (ASC) and memory B cells (MB)C. Aim 2 will test the hypothesis that blockade of huCD21 receptor impairs formation of autoreactive germinal center (GC) derived ASC and MBC in lupus.