Evaluation of Labeled Anti-B7-H3 Antibodies as Potential Theragnostic Agents for Cancer Immunotherapy

Authors

• B Fernandes
• CP Olkowski
• F Basuli
• B Ghaemi
• PL Choyke
• FI Lin
• O Jacobson

Abstract

One promising immunomodulatory target for immune resistance is the B7-H3 protein (4Ig and 2Ig-B7-H3 isoforms), which is overexpressed in various solid tumors with minimal expression in healthy tissues. This study aimed to evaluate the potential of radiolabeled anti-B7-H3 antibodies (Ab-1 and Ab-2) as theragnostic agents for positron emission tomography (PET) and radioimmunotherapy of B7-H3-positive tumors. In vitro characterization of the 89Zr-DFO-Ab-1 and 89Zr-DFO-Ab-2 was performed as well as in vivo studies such as PET and biodistribution in B7-H3-positive and negative xenograft models. Radiotherapy studies were carried out with Ab-1 radiolabeled to 177Lu-DOTA. Ab-1 demonstrated higher specificity and affinity for the 4Ig-B7-H3 isoform (Kd=2nM) than for 2Ig-B7-H3 (Kd=26nM). Ab-2 showed similar affinity to the 4Ig-B7-H3 isoform (Kd=3nM) but no binding to 2Ig-B7-H3. Both 89Zr-DFO-Ab-1 and 89Zr-DFO-Ab-2 demonstrated good affinity for B7-H3-positive cells (Kd= 1.5nM and 4nM, respectively), however, 89Zr-DFO-Ab-1 showed higher internalization rate (34%) than 89Zr-DFO-Ab-2 (17%). PET studies confirmed favorable pharmacokinetic properties of 89Zr-DFO-Ab-1 with rapid blood clearance compared to 89Zr-DFO-Ab-2. A significant reduction in the tumor uptake was observed at 96 hours post-injection of 89Zr-DFO-Ab-1, but not for 89Zr-DFO-Ab-2. The unusual clearance of radiolabeled Ab-1 led to its selection for radiotherapy studies. 177Lu-DOTA-Ab-1 resulted in significant tumor shrinkage (>46%) compared to controls, but some toxicity was observed, leading to 17% survival. Overall, 89Zr-DFO-Ab-1 has high specificity and favorable pharmacokinetics, making it a promising imaging agent for B7-H3-positive tumors. 177Lu-DOTA-Ab-1 showed promising therapeutic effects, but the evaluation of the toxicity and optimization of the effective therapy dose is underway.

Scientific Focus Area: Cancer Biology

This page was last updated on Tuesday, August 6, 2024