;)
The field of inflammation and immunology has historically revolved around monotherapy—single cytokine blockade or single pathway inhibition. IL-23 inhibitors, TNF-alpha antagonists, and IL-6 receptor blockers: each represent a single point of intervention. Today, early-stage companies are investing resources in multimodal pathways impacting multiple targets simultaneously. Engineered cytokine variants and checkpoint modulation are becoming standard.
The evidence supporting this shift is empirical. While TNF-alpha blockade and IL-6 inhibition remain effective, approximately 30% of treated rheumatoid arthritis patients fail to respond—a ceiling that single-target therapies have not crossed. (Alsayb et al., 2025). The problem isn’t that these mechanisms don’t work; it’s that they address only one component of inflammatory pathology. Rheumatoid arthritis involves multiple pro-inflammatory drivers: TNF-alpha drives inflammation; IL-6 stimulates B cell and T cell differentiation and IL-17 amplifies Th17 responses. When one cytokine is blocked, residual activity through other pathways can sustain disease activity despite adequate inhibition of the original target. Blocking one pathway doesn’t prevent compensation through other pathways.
Bispecific antibodies exemplify a multimodal strategy. These engineered molecules simultaneously engage two distinct targets, enabling more precise immune modulation than traditional monoclonal antibodies.
ABT-122 (AbbVie), a bispecific antibody targeting TNF-alpha and IL-17A, demonstrated clinical efficacy comparable to adalimumab in a randomized, double-blind Phase 2 study of methotrexate-inadequate-responder rheumatoid arthritis. (Xu et al., 2018).
In inflammatory bowel disease, dual cytokine blockade has also shown promise. The VEGA trial (NCT03662542) evaluated guselkumab (anti-IL-23) plus golimumab (anti-TNF-alpha) versus either guselkumab or golimumab monotherapy in moderately to severely active ulcerative colitis. Combination therapy produced higher clinical response and endoscopic improvement rates at week 12 than either single agent, with sustained benefits through week 38. (Feagan et al., 2023).
Complement pathway inhibition has emerged as a validated therapeutic paradigm. The complement system—a cascade of plasma proteins mediating innate immunity—amplifies inflammation in multiple autoimmune conditions. Factor B inhibition and C5a antagonism are now validated mechanisms, with Novartis’ iptacopan receiving FDA accelerated approval for IgA nephropathy in 2024, establishing complement inhibition as a regulatory-endorsed strategy. In the APPLAUSE-IgAN Phase 3 trial, iptacopan reduced proteinuria versus placebo in adults with primary IgA nephropathy, supporting its use as an oral factor B inhibitor targeting the alternative complement pathway. (Novartis, 2024).
Intracellular pathway targeting continues to mature. JAK1-selective inhibition (rather than pan-JAK blockade) offers reduced off-target effects. Upadacitinib (Rinvoq), a selective JAK1 inhibitor, is approved across multiple immune-mediated inflammatory diseases and is being evaluated in Phase 3 trials for systemic lupus erythematosus, reflecting recognition that pathway selectivity can improve safety profiles without sacrificing efficacy. (AbbVie, 2023).
The next horizon is engineered cytokines. IL-2 variants engineered to preferentially expand regulatory T cells while sparing effector T cells and NK cells are in early-mid-stage clinical development for lupus and in earlier translational stages for Type 1 diabetes, representing an approach that enhances anti-inflammatory mechanisms rather than simply blocking proinflammatory ones. Preclinical IL-2 muteins have been shown to preferentially expand regulatory T cells and reverse autoimmune pathology in animal models, while low-dose IL-2 regimens in clinical studies (such as DILT1D in Type 1 diabetes and multi-centre Phase 2 trials in systemic lupus erythematosus) have demonstrated selective expansion of regulatory T cells with associated improvements in disease activity. (Khoryati et al., 2020; Waldron-Lynch et al., 2014; Humrich et al., 2022).
This is not incremental progress; it’s methodological transformation. The future of inflammation immunology isn’t about blocking one pathway more effectively. It’s about orchestrating multiple simultaneous interventions—blockade, immune tolerance enhancement, pathway selectivity—tailored to each patient’s immune phenotype.
References:
AbbVie. (2023, March 23). AbbVie advances upadacitinib (RINVOQ®) to Phase 3 clinical trials in systemic lupus erythematosus. https://news.abbvie.com/2023-03-23-AbbVie-Advances-Upadacitinib-RINVOQ-R-to-Phase-3-Clinical-Trials-in-Systemic-Lupus-Erythematosus
Feagan, B. G., Sands, B. E., Sandborn, W. J., Germinaro, M., Vetter, M., Shao, J., … & Ritter, T. (2023). Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial. The Lancet Gastroenterology & Hepatology, 8(4), 307–320.
Humrich, J. Y., et al. (2022). Low-dose interleukin-2 therapy in active systemic lupus erythematosus: A multicentre, double-blind, randomized, placebo-controlled phase II trial. Annals of the Rheumatic Diseases, 81(12), 1685–1695.
Khoryati, L., et al. (2020). An IL-2 mutein engineered to promote expansion of regulatory T cells resolves autoimmunity in preclinical models. Science Immunology, 5(50), eaba5264.
Novartis. (2024, August 7). Fabhalta® (iptacopan) receives FDA accelerated approval for reduction of proteinuria in adults with IgA nephropathy. https://www.novartis.com/news/media-releases/novartis-receives-fda-accelerated-approval-fabhalta-iptacopan-first-and-only-complement-inhibitor-reduction-proteinuria-primary-iga-nephropathy-igan
Waldron-Lynch, F., et al. (2014). Rationale and study design of the adaptive study of IL-2 dose-finding in type 1 diabetes (DILT1D). BMJ Open, 4(6), e005559.
Xu, T., et al. (2018). ABT-122, a bispecific dual variable domain immunoglobulin targeting tumor necrosis factor and interleukin-17A, in patients with rheumatoid arthritis with an inadequate response to methotrexate: A randomized, double-blind study. Arthritis & Rheumatology, 70(10), 1710–1721.
