In a groundbreaking phase 1 clinical trial, researchers have explored the safety and pharmacokinetics of PF-06835375, a novel antibody targeting C-X-C chemokine receptor type 5 (CXCR5). This study, published in Arthritis Research & Therapy, marks a significant step forward in the treatment of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).
The trial was a first-in-human, randomized, double-blind, placebo-controlled study with two parts. In Part A, patients received escalating single intravenous doses of PF-06835375 or placebo. In Part B, patients received repeat subcutaneous doses on day 1 and 29. Participants, aged 18-70 with SLE or RA, totaled 73, with 84.9% experiencing mostly mild to moderate treatment-emergent adverse events (TEAEs) and 9.7% experiencing serious adverse events. Pharmacokinetic analyses showed a variable half-life for PF-06835375, while pharmacodynamic results demonstrated up to 99.6% depletion of B and cTfh cells. Functional effects were further assessed using Tetanus/Diphtheria (Td) and Meningococcal B (MenB/Trumenba™) vaccines, showing effective immune modulation and downregulation of B cell-related genes.
B cell and T cell dysregulation plays a crucial role in the pathology of SLE and RA. In SLE, T cells amplify inflammation by secreting pro-inflammatory cytokines, which in turn drive B cells to produce autoantibodies, perpetuating the disease by accumulating autoreactive memory T cells. In RA, B cells contribute to disease pathogenesis by secreting rheumatoid factors, anti-citrullinated protein antibodies, and pro-inflammatory cytokines. PF-06835375 is a humanized, afucosyl immunoglobulin G1 antibody targeting the C-X-C chemokine receptor type 5 (CXCR5) found on B cells, Tfh cells, and circulating Tfh-like (cTfh) cells. This antibody is being developed for treating autoimmune diseases by depleting CXCR5-positive B and Tfh cells and inhibiting C-X-C motif chemokine ligand 13-dependent signaling. PF-06835375 represents a novel strategy for managing SLE and RA.
PF-06835375 targets interleukin-1 receptor-associated kinase 4 (IRAK4), a key protein in the signaling pathways of the innate immune system. By inhibiting IRAK4, PF-06835375 disrupts the downstream signaling cascades that lead to the production of pro-inflammatory cytokines and other mediators of inflammation. This inhibition helps to reduce the chronic inflammation characteristic of autoimmune diseases, thereby potentially improving disease control and reducing symptoms without broadly suppressing the immune system.
Monoclonal antibodies have revolutionized the treatment for SLE and RA by providing targeted, effective, and safer therapeutic options. These biologics precisely target-specific molecules involved in disease pathogenesis, reducing inflammation and autoimmunity more effectively than traditional treatments. This precision leads to significant reductions in disease activity and symptom severity, enhancing patient outcomes and quality of life by reducing pain and improving physical function. Additionally, monoclonal antibodies offer alternative treatments for patients who do not respond to conventional therapies, and their targeted nature minimizes broad immunosuppressive effects and associated side effects.
The current phase 1 trial supports the continued development of PF-06835375. Its ability to selectively target and deplete immune cells involved in autoimmune diseases holds significant promise for future therapies aimed at SLE and RA. As research progresses, there is hope that PF-06835375 could provide a new approach to managing and potentially relieving the burden of autoimmune diseases, bringing much-needed relief to millions worldwide.
Reference
Cohen S, Beebe JS, Chindalore V, Guan S, Hassan-Zahraee M, Saxena M, et al. A Phase 1, randomized, double-blind, placebo-controlled, single- and multiple-dose escalation study to evaluate the safety and pharmacokinetics/pharmacodynamics of PF-06835375, a C-X-C chemokine receptor type 5 directed antibody, in patients with systemic lupus erythematosus or rheumatoid arthritis. Arthritis Res Ther. 2024 Jun 6;26(1):117.