Therapeutic potential of antibody-drug conjugates possessing bifunctional anti-inflammatory action in the pathogenies of rheumatoid arthritis

Abstract

In an age where there is a remarkable upsurge in developing precision medicines, antibody-drug conjugates (ADCs) have emerged as a progressive therapeutic strategy. ADCs typically consist of monoclonal antibodies (mAb) conjugated to the cytotoxic payloads by utilizing a linker, combining the benefits of definitive target specificity of mAbs and potent killing impact of payload to achieve precise and efficient elimination of target cells. In addition to their well-established role in oncology, ADCs are currently demonstrating encouraging potential in addressing the unmet requirements in the treatment of autoimmune conditions such as rheumatoid arthritis (RA). Prevalent long-term autoimmune disease RA costs billions of dollars annually but still, there is a lack of precision-targeted therapeutics with minimal side effects. This review provides an overview of the RA pathogenesis, pre-existing therapies, and their limitations, the introduction of ADCs in RA treatment, the mechanism of ADCs, and a summary of ADCs in preclinical and clinical trials. Based on the literature we also propose a strategy in ADC synthesis, which may increase the efficiency in targeting multifactorial diseases like RA. We propose to utilize DMARDs (Disease-modifying anti-rheumatic drugs), the first-line treatment for RA, as a payload for ADC synthesis. DMARDs are the only class of medication that limits the disease progression, but their efficacy is limited due to off-target toxicities. Hence, utilizing them as payload will help to deliver them directly at the targeted site, reducing their off-target toxicity, which in turn will increase their efficiency in targeting disease. Also, as mAbs are not sufficient to achieve remission, they are given in combinations with DMARDs. Hence, synthesizing ADCs may reduce the multiple and higher dosages given to patients, which in turn may enhance patient compliance.

Keywords: Antibody-drug conjugates; Inflammation; Monoclonal antibodies; Disease modifying anti-rheumatoid drugs; Immunomodulation; Rheumatoid arthritis.

Fig. 1

Pathophysiological microenvironment in inflamed synovium to demonstrate the pathogenesis of RA. Arginine to citrulline conversion (citrullination) occurs due to several factors, including genetic susceptibility, smoking, and pre-existing infections. APCs present these citrullinated proteins as self-antigens to T cells, leading to the activation of CD4⁺ Th cells. These activated Th cells get differentiated into Th1 and Th17 and secrete pro-inflammatory cytokines such as TNF-α, IL-17, and IL-1. These cytokines activate other immune cells such as macrophages and recruit them to synovium. As a result of inflammation, the extracellular matrix is destroyed and collagenase release, MMP synthesis, and FLS activation are triggered. T cells also help B-cells to generate auto-antibodies named RF and ACPA. These antibodies bind to citrullinated proteins and form immune complexes that exacerbate inflammation and lead to the development of pannus, deterioration of cartilage, and joint deformities. RA-rheumatoid arthritis; APCs-antigen presenting cells; CD4- clusters of differentiation 4; Th-T-helper; TCR- T-cell receptor; MHC- major histocompatibility complex; RF- rheumatoid factors; ACPA- anti-citrullinated protein antibodies; TNF-α- tumor necrosis factor; IL- interleukin; MMP- matrix metalloproteinases; FLS- fibroblast-like synoviocytes; RANK; Receptor activator of nuclear factor κ B

Fig. 2

Limitations associated with conventional disease-modifying anti-rheumatic drugs (DMARDs) and biological DMARDs, combination therapy, and imperative for targeted delivery of conventional DMARDs for effective management of rheumatoid arthritis

Fig. 3

Schematic representation of desired attributes and components of ADCs. DAR-drug to antibody ratio; ADCs- antibody-drug conjugates

Fig. 4

Strategy to overcome the limitations possessed by DMARDs and monoclonal antibodies in RA treatment. By merging the specificity of mAbs specific for RA and with the use of potent anti-rheumatoid drugs DMARDs as a payload, ADCs can accomplish effective targeting and destruction of target B cells, T cells, macrophages, or immunomodulators involved in the pathogenesis of RA. As per the mechanism of ADCs, DMARDs can be directly delivered to targeted cells by attachment of antibodies to particular antigens present on the surface of targeted cells. Once bound, the ADC enters the cell through endocytosis, creating an endosome. The endosome evolves into endolysosomes, where the DMARDs will be discharged outside the cell because of the acidic conditions or enzymatic degradation. This process ensures accurate release of the DMARDs inside the targeted cell. The DMARDs can then disrupt crucial cell functions, ultimately prompting cell death, hence providing high precision, minimizing off-target effects, and boosting the therapeutic effectiveness