Targeting Extracellular Vesicles to the Arthritic Joint Using a Damaged Cartilage-Specific Antibody

Abstract

The targeted delivery of therapies to diseased tissues offers a safe opportunity to achieve optimal efficacy while limiting systemic exposure. These considerations apply to many disease indications but are especially relevant for rheumatoid arthritis (RA), as RA is a systemic autoimmune disease which affects multiple joints. We have identified an antibody that is specific to damaged arthritic cartilage (anti-ROS-CII) that can be used to deliver treatments specifically to arthritic joints, yielding augmented efficacy in experimental arthritis. In the current study, we demonstrate that scaffolds enriched with bioactive payloads can be delivered precisely to an inflamed joint and achieve superior efficacy outcomes consistent with the pharmacological properties of these payloads. As a scaffold, we have used extracellular vesicles (EVs) prepared from human neutrophils (PMNs), which possess intrinsic anti-inflammatory properties and the ability to penetrate inflamed arthritic cartilage. EV fortified with anti-ROS-CII (EV/anti-ROS-CII) retained anti-ROS-CII specificity and bound exclusively to the damaged cartilage. Following systemic administration, EV/anti-ROS-CII (a) exhibited the ability to localize specifically in the arthritic joint in vivo and (b) was able to specifically target single (viral IL-10 or anti-TNF) or combined (viral IL-10 and anti-TNF) anti-inflammatory treatments to the arthritic joint, which accelerated attenuation of clinical and synovial inflammation. Overall, this study demonstrates the attainability of targeting a pro-resolving biological scaffold to the arthritic joint. The potential of targeting scaffolds such as EV, nanoparticles, or a combination thereof alongside combined therapeutics is paramount for designing systemically administered broad-spectrum of anti-inflammatory treatments.

Perspectives in Manipulating EVs for Therapeutic Applications: Focus on Cancer Treatment

“…Thereby, they may be considered as physiological targeting mediators ( Figure 1 ). Furthermore, the use of antigen-specific antibodies or LCs greatly increases the specificity of tissue targeting by EVs [ 117 ].…”

The Role and Impact of Extracellular Vesicles in the Modulation and Delivery of Cytokines during Autoimmunity

“…With the addition of a range of EV surface receptors, such as immunoglobulins, lectins, MHC receptors, and viral proteins, it is possible to promote the selective recruitment of EVs to a specific tissue, site of injury, or cell population [ 125 ]. In fact, work from our group has demonstrated that neutrophil-derived EVs, which display anti-inflammatory activity, can be loaded with therapeutic cargo including anti-TNF-α as well as IL-10 and targeted to arthritic joints using cartilage specific antibodies to improve experimental arthritis ( Figure 2 ) [ 151 , 152 , 153 ].…”

“…Using a variant of anti-ROS-CII, bound to viral IL-10 via a matrix metalloproteinase cleavable linker region (anti-ROS-CII-vIL-10), EVs were able to release an anti-inflammatory payload upon arrival to the injured joint. PMN-EVs co-engineered to express both anti-ROS-CII-vIL-10 and anti-TNF antibodies were shown to greatly reduce pro-inflammatory cytokine gene expression and enhance cartilage anabolism; to the extent whereby CIA joints treated with modified PMN-EVs were similar to healthy joints based on gross architectural appearance [ 151 , 154 ].…”

Early detection of osteoarthritis in the rat with an antibody specific to type II collagen modified by reactive oxygen species

“…We previously developed a panel of human single chain fragment variable (scFv) that bind speci cally to oxidative post-translationally modi ed collagen type II (oxPTM-CII) (12). We showed that anti-oxPTM-CII: i) binds speci cally to arthritic cartilage from patients with RA and OA; ii) stains cartilage in murine models of in ammatory arthritis (antigen induced arthritis (AIA) and OA, namely DMM; iii) localizes in the arthritic joint in vivo in a mouse model of AIA and DMM following systemic administration of labelled anti-oxPTM-CII with Alexa Fluor 680 or Cy5.5 (12,13); and iv) was able to target therapeutic scaffold speci cally to arthritic joint (14).…”