Differential Effects of Predosing on Tumor and Tissue Uptake of an¹¹¹In-Labeled Anti-TENB2 Antibody–Drug Conjugate

Abstract

TENB2, also known as tomoregulin or transmembrane protein with epidermal growth factor-like and 2 follistatin-like domains, is a transmembrane proteoglycan overexpressed in human prostate tumors. This protein is a promising target for antimitotic monomethyl auristatin E (MMAE)-based antibody-drug conjugate (ADC) therapy. Nonlinear pharmacokinetics in normal mice suggested that antigen expression in normal tissues may contribute to targeted mediated disposition. We evaluated a predosing strategy with unconjugated antibody to block ADC uptake in target-expressing tissues in a mouse model while striving to preserve tumor uptake and efficacy. Methods: Unconjugated, unlabeled antibody was preadministered to mice bearing the TENB2-expressing human prostate explant model, LuCaP 77, followed by a single administration of 111 In-labeled anti-TENB2-MMAE for biodistribution and SPECT/CT studies. A tumor-growth-inhibition study was conducted to determine the pharmacodynamic consequences of predosing. Results: Preadministration of anti-TENB2 at 1 mg/kg significantly increased blood exposure of the radiolabeled ADC and reduced intestinal, hepatic, and splenic uptake while not affecting tumor accretion. Similar tumor-to-heart ratios were measured by SPECT/CT at 24 h with and without the predose. Consistent with this, the preadministration of 0.75 mg/kg did not interfere with efficacy in a tumor-growth study dosed at 0.75 mg or 2.5 mg of ADC per kilogram. Conclusion: Overall, the potential to mask peripheral, nontumor antigen uptake while preserving tumor uptake and efficacy could ameliorate toxicity and may significantly affect future dosing strategies for ADCs.

Engineered antibody fragments for immuno-PET imaging of endogenous CD8 + T cells in vivo

“…Furthermore, the concept of blocking the antigen sink has repercussions in the field of therapeutic antibody-drug conjugates. For example, predosing injections were used to block the antigen sink of tomoregulin, or TENB2, a transmembrane protein overexpressed in prostate tumors, to increase the therapeutic index of the monomethyl auristatin E-conjugated anti-TENB2 antibody (28). This study also highlights the fine balance between efficient blocking of the antigen sink vs. displacing the tumor uptake.…”

An Effective Immuno-PET Imaging Method to Monitor CD8-Dependent Responses to Immunotherapy

“…spleen and lymph nodes, the optimal protein dose will be dependent on the immunotherapeutic mechanism of action and the ability to consistently target intratumoral CD8 + T cells will rely on a fine balance between blocking the CD8 antigen sink and displacing tumor uptake. The importance of protein dose for tumor epitope targeting has been demonstrated previously where a natural antigen sink exists in imaging studies targeting HER2 (28), neuropilin-1 (29), and epidermal growth factor receptor (30), and antibody-drug conjugate studies targeting TENB2 (31). A recent publication by Muylle at al.…”

Absorption, Distribution, Metabolism, and Excretion Considerations for the Development of Antibody-Drug Conjugates

“…In contrast, antibodies are restricted primarily to plasma and extracellular fluids and are concentrated at tissues that express the target antigen, especially tumors in xenograft mouse studies (Alley et al, 2009;Boswell et al, 2012;Boswell et al, 2013). For an ADC, the pharmacokinetics and biodistribution have been noted to be more like an antibody than a small molecule.…”