(M-007) Intravenous Immunoglobulin G (IVIG)-Monoclonal Antibody (mAb) Drug Interactions: Time for Model-Informed Clinical Guidance?

PARIDHI GUPTA – Pharmaceutical Sciences – University of Tennessee Health Science Center; Vivaswath Ayyar – Pharmaceutical Sciences – University at Buffalo, State University of New York

Objectives: Concomitant use of intravenous immunoglobulin (IVIG) alongside monoclonal antibodies (mAbs) or bispecific T-cell engagers (TCEs) is increasingly encountered in clinical practice, particularly in patients with autoimmune diseases, B-cell malignancies, primary immune deficiencies, or those undergoing organ transplantation. While these therapies offer clinical benefits in specific contexts, their pharmacologic interplay—particularly via the neonatal Fc receptor (FcRn)—warrants further evaluation to optimize efficacy, safety, and patient outcomes. We employed a mechanistic, model-based approach to investigate the impact of IVIG dose and frequency, timing of administration, and altered endogenous IgG levels due to disease or concomitant therapies on the PK and PD properties of select therapeutic mAbs.

Methods: An established mechanistic model of IgG disposition and IVIG effects in mice [1] was adapted and requalified using human data to describe FcRn-mediated competition among endogenous IgG, therapeutic mAbs, pathogenic IgG, and administered IVIG. The model incorporated zero-order synthesis of endogenous IgG in the central compartment and FcRn binding and recycling in the peripheral compartment, with unbound IgG undergoing first-order catabolism. It was used to (i) relate total serum IgG kinetics with endogenous and/or pathogenic IgG lowering in autoimmune diseases [2-5], and (ii) predict the impact of high-dose IVIG on the PK and PD (Weislab and CH50 assays) of tesidolumab (anti-C5 mAb) in renal transplant recipients [6]. Simulations examined two clinical trial scenarios: (i) the effect of flat-dose IVIG for infection prophylaxis in multiple myeloma patients on bispecific mAb PK [7], and (ii) PK consequences of rituximab–IVIG co-therapy for transplant desensitization [8].

Results: Serum IgG kinetics were reasonably well described following 2 g/kg IVIG in patients from three clinical studies [2-4]. The model reproduced tesidolumab PK profiles with and without IVIG, accurately predicting a 37% reduction in mean exposure and a 70% increase in clearance during IVIG coadministration – explaining observed differences in PD response. In pemphigus vulgaris patients receiving 2 g/kg IVIG [4], total IgG increases (231% and 144% of baseline at weeks 1 and 2) were predicted accurately. Model-predicted reductions in endogenous IgG (%) aligned with published pathogenic autoantibody lowering [5]. Model simulations enacted clinically relevant IVIG–mAb co-therapy scenarios and systematically explored the influence of IVIG dose, timing, and IgG dynamics on mAb PK in feasible patient settings.

Conclusions: Multiple factors must be considered when implementing IVIG–mAb/TCE co-therapy. Whether used for immunosuppression or IgG replacement, IVIG can disrupt FcRn-mediated recycling, thereby altering biologic PK, efficacy, and safety. Model-informed strategies for timing, dosing, and monitoring are critical to optimizing therapeutic outcomes. The rise of anti-FcRn therapies further underscores the value of mechanistic modeling in guiding complex treatment decisions when co-therapy is warranted.

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3. Kuitwaard K, et al. Ann Neurol. 2009;66:597–603.
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6. Jordan SC, et al. Am J Transplant. 2020;20:2581–8.
7. Marneni N, et al. Blood. 2023;2:142–3778.
8. Vo AA, et al. N Engl J Med. 2008;359:242–51.

Keywords: intravenous immunoglobulin G, monoclonal antibody, mechanistic modeling