Total threshold cytotoxicity of therapeutic antibodies for selective destruction of pathogenic memory T cells: implications for immunotherapy of autoimmune and allergenic disorders

ABSTRACT

Introduction: Pathogenic memory CD4⁺ T cells are the mainspring of autoimmune and allergic disorders, suggesting that effective pathogenetic immunotherapy should be primarily directed onto their direct inactivation without affecting normal cells.

Areas covered: A novel immunotherapeutic concept is proposed that applies suboptimal doses of several cytotoxic antibodies (Abs) against membrane antigens (Ags) (such as CD4, СD45RO, СD69, CD103, CD27, CD38, DR, etc.) with a view to achieve a threshold density of immune complexes on pathogenic memory CD4⁺ T cells for their selective elimination. During disease exacerbations, a complex Ab formulation could be applied to combine Abs against CD4, СD45RO, and СD69 to selectively destroy both activated memory CD4⁺ T cells located in lymphoid tissues and resident memory CD4⁺ T cells present in local inflammatory sites in situ. In contrast, normal T cells are spared from destruction as being recognized only by some Abs leading to Ab-Ag complexes below cytolytic threshold levels. Inactivation of pathogenic CD4⁺ T cells will also withdraw T helper support to pathogenic memory B cells and memory CD8⁺ T cells, thus effectively diminishing their activity.

Expert opinion: The described approach benefits from universality and potential availability of a vast library of monoclonal Abs with relevant specificity.

GraphicalAbstract

KEYWORDS:

• Therapeutic antibody
• antibody-mediated cytotoxicity
• immune complex
• pathogenic memory T cell
• autoimmune disease
• allergy

Article Highlights

• Pathogenic memory CD4⁺ T cells are the mainspring of autoimmune and allergic disorders.

• Simultaneous administration of suboptimal doses of cytotoxic antibodies against CD4, СD45RO, and СD69 molecules could selectively destroy pathogenic memory helper T cells with minimal side effects in clinical settings.

• Inactivation of pathogenic CD4⁺ T cells could withdraw T helper support to pathogenic B cells and CD8⁺ T cells, thus effectively eliminating other pathogenic mechanisms.

• A novel concept is proposed, which can potentially use a plethora of available Ags against surface markers (such as CD103, CD27, CD38, DR, etc.) expressed on pathogenic T lymphocytes as targets for therapeutic Abs in order to attain critical cytotoxicity levels necessary for selective elimination of pathogenic T cells.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.