Disrupting B and T-cell collaboration in autoimmune disease: T-cell engagers versus CAR T-cell therapy?

Abstract

B and T cells collaborate to drive autoimmune disease (AID). Historically, B- and T-cell (B-T cell) co-interaction was targeted through different pathways such as alemtuzumab, abatacept, and dapirolizumab with variable impact on B-cell depletion (BCD), whereas the majority of patients with AID including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and organ transplantation benefit from targeted BCD with anti-CD20 monoclonal antibodies such as rituximab, ocrelizumab, or ofatumumab. Refractory AID is a significant problem for patients with incomplete BCD with a greater frequency of IgD-CD27+ switched memory B cells, CD19+CD20- B cells, and plasma cells that are not directly targeted by anti-CD20 antibodies, whereas most lymphoid tissue plasma cells express CD19. Furthermore, B-T-cell collaboration is predominant in lymphoid tissues and at sites of inflammation such as the joint and kidney, where BCD may be inefficient, due to limited access to key effector cells. In the treatment of cancer, chimeric antigen receptor (CAR) T-cell therapy and T-cell engagers (TCE) that recruit T cells to induce B-cell cytotoxicity have delivered promising results for anti-CD19 CAR T-cell therapies, the CD19 TCE blinatumomab and CD20 TCE such as mosunetuzumab, glofitamab, or epcoritamab. Limited evidence suggests that anti-CD19 CAR T-cell therapy may be effective in managing refractory AID whereas we await evaluation of TCE for use in non-oncological indications. Therefore, here, we discuss the potential mechanistic advantages of novel therapies that rely on T cells as effector cells to disrupt B-T-cell collaboration toward overcoming rituximab-resistant AID.

Keywords: CAR T-cell therapy; T-cell engagers; rheumatoid arthritis; rituximab; systemic lupus erythematosus.

Graphical Abstract

Figure 1.

Pathways of B–T-cell co-stimulation and trials of therapeutic agents. Molecular pairings are explained in Table 1. Drugs that target co-stimulation are outlined here. Dapirolizumab is an anti-CD40L mAb, currently in phase III study in SLE (NCT04294667). Bleslumab is an IgG4 mAb that targets CD40 which underwent phase II trial in plaque psoriasis with no clinical improvement compared to placebo [4], and demonstrated non-inferiority compared with standard of care for acute rejection in renal transplant recipients [5]. Iscalimab is another anti-CD40 mAb which is undergoing phase II trial in SLE and Sjogren’s Syndrome (NCT03656562, NCT04541589). Abatacept inhibits CD80/86 to prevent engagement with CD28 and is approved for use in RA but failed to meet the primary endpoint in the lupus nephritis phase III trial. AMG 557, anti-ICOSL antibody, underwent phase II trial in SLE and a newer therapy inhibiting ICOSL and BAFF is undergoing phase II trial (NCT04058028). PD-1 agonist, Peresolimab demonstrated modest improvement in disease activity in a phase II trial for patients with RA. Image created using Biorender.com

Figure 2.

Historical timeline of therapies that target B–T-cell collaboration in autoimmune disease. These agents were designed either to deplete B cells and/or disrupt the B–T-cell collaboration. The top row denotes the target antigen, the second row demonstrates the drugs that have undergone clinical trial (later two, t are yet to undergo clinical trial in AID). The third row represents therapies that interrupt B–T-cell networking and the fourth row represents treatments that employ T cells as effector cells. Text in italics under CD20 represents other approved anti-CD20 mAbs, *denotes pending approval

Figure 3.

Life cycle of B lineage cells. B cells originate in the bone marrow and migrate through peripheral circulation into lymphoid tissues such as lymph nodes and the spleen. Naïve B cells mature into memory B cells which then differentiate into switched memory B cells, SwMBC (IgD⁻,CD27+), or double negative memory B cells (DN MBC; IgD⁻, CD27⁻) entering the peripheral circulation or plasma blasts (PBs) and plasma cells (PCs) a majority of which reside in the bone marrow, tissues, and inflammatory sites. Proportions of CD19⁺CD20⁺ versus CD19⁺CD20⁻ B cells are demonstrated pictorially within each subpopulation. Anti-CD20 monoclonal antibodies such as rituximab may not completely deplete CD19⁺CD20⁺ B cells in tissue and do not target CD19⁺CD20⁻ B cells, therefore, alternative strategies of depletion including CD19 targeting approaches may help to overcome rituximab resistance in autoimmunity

Figure 4.

Evolution of CARs across the generations. All CARs have a single chain variable region of a mAb. (A) first-generation CARs contain an intracellular signaling domain of CD3 zeta chain alone; (B) second-generation includes a single co-stimulatory domain (CD28 or 4-1BB); (C) third-generation CARs combine two of the above co-stimulatory domains; and (D) fourth-generation CARs are diversified in that they can express cytokines. Image created using BioRender.com

Figure 5.

Selected TCE formats in a schematic representation used for T-cell redirecting therapies. (A) Blinatumomab, tandem scFv (single chain variable fragment) (BiTE) format. (B) Mosunetuzumab, IgG-based-TCE with monovalent binding using a native antibody structure with 1 Fab arm to bind CD20 (target antigen) and 1 Fab arm to bind CD3 on T cells, combined with the KiH technology as demonstrated in the CH3 domain to achieve heavy chain heterodimerization. (C) Epcoritamab, IgG-based TCE with point mutations in each Fc region (CH3 domain) to allow controlled Fab-arm exchange, termed DuoBody®. (D) Glofitamab, bivalent binding to increase the avidity of TCE binding to the target antigen, CD20, with additional KiH and CrossMab^VH-VL with charge interactions using variable regions. Image created using Biorender.com

Figure 6.

The potential effect of immunosuppressive treatments on T-cell effector function. Mycophenolate mofetil (MMF) as per the bottom panel, results in fewer T cells to serve as effector cells for therapies such as CD19 TCE and CD19 CAR T cells. MMF can directly reduce the number of T cells and impair their activation and reduce their cytotoxicity against target B cells with lower release of perforin and granzyme molecules. Image created using Biorender.com