(S-111) Re-Purposing Bispecific Antibodies in Autoimmune Diseases: MIDD Based Dose Optimization Strategies

Jennifer Sheng, PhD – College of Pharmacy – University of Michigan; Tongli Zhang – Dept of Pharmacology, Physiology and Neurobiology – University of Cincinnati; Keith Zhu – Princeton High School

Objectives: Bispecific antibodies (bsAbs) were originally developed in oncology and are now being explored in autoimmune diseases (AD), hypothesized with similar mechanism of actions, eg, deleting B cell and plasma cells by activating T cells. Dose selection in this context requires careful adaptation from oncology experience, with distinct considerations for disease burden, patient safety, and beyond. This study aims to:1). present the landscape analysis of ongoing bsAb trials in autoimmune diseases; 2). propose a dose selection and recommendation framework; and 3). provide case examples of Teclistamab (BCMA×CD3, Tecl) and Blinatumomab (CD19×CD3, Blin).

Methods: Currently, there are 27 bsAb clinical trials for AD from ClinicalTrials.gov (as of April 2025) [1]. Trial phases, drug initial intended indications, administration routes, and AD indications were summarized. Compounds were classified as either repurposed from oncology (approved or in oncology trials) or de novo in autoimmune. Additionally, a comprehensive yet practical approach with four complementary pillars is proposed for dose selection & optimization, aiming to accelerate precision dosing in AD. Also, two case studies—Tecl and Blin—were used to illustrate translational modeling, exposure simulations, and their clinical implications. The published PPK models were from FDA approved drug access [2]. Exposure simulations and PKPD analyses were conducted with RStudio (version 4.5.0). The QSP model for systemic lupus erythematosus was adapted from Gao, et al [3].

Results: There are 21 unique bsAbs investigated in 27 clinical trials [1]. Of these: 40.7% are repurposed from oncology (e.g., tecl, blin, mosunetuzumab), and 59.3% are de novo in AD; 81.5% of trials are in early development (Phase I/II), and 18.5% have reached Phase III. The four pillars are: leveraging the contemporary landscape data, benchmarking the “targeted” in vitro EC50/90 concentrations under various dosage regimen, translating preclinical PKPD relationship to the intend treated patients, and applying mini-QSP modeling to new indications. Tecl, repurposed from multiple myeloma, was administered SC at doses ranging from 0.03 to 1.5 mg/kg in autoimmune studies [4, 5]. PPK and PKPD simulations suggested exposures within “relevant” efficacy range, possibly requiring less frequent or lower dosing in autoimmune. Blin, originally dosed as 5 or 15ug/m2/day or 28 µg/day for patients with ALL, demonstrated effective B-cell reset at ~1000-fold lower doses in RA [6]. QSP modelling illustrated our strategy of adapting the existing QSP models for the purpose of dose selection.

Conclusions: In the context of “repurposing” oncology bsAbs for autoimmune, our proposed MIDD approach and the exemplified case studies, would accelerate the dose optimization and reduce the development timelines.

Citations: References
1. ClinicalTrials.gov. https://clinicaltrials.gov/, review, accessed March 2025.
2. FDA Drugs Approved, https://www.accessdata.fda.gov/, accessed March 2025.
3. Gao, Xin, et al. "Dynamically modeling the effective range of IL-2 dosage in the treatment of systemic lupus erythematosus." Iscience 25.9 (2022).
4. Alexander T, Krönke J, Cheng Q, et al. Teclistamab-Induced Remission in Refractory Systemic Lupus Erythematosus. N Engl J Med. 2024;391(9):864–866.
5. Hagen M, Bucci L, Böltz S, et al. BCMA-Targeted T-Cell–Engager Therapy for Autoimmune Disease. N Engl J Med. 2024;391(9):867–869.
6. Bucci L, Hagen M, Rothe T, et al. Bispecific T cell engager therapy for refractory rheumatoid arthritis. Nat Med. 2024;30(6):1593–1601.

Keywords: autoimmune; bispecifics; MIDD;