Abstract 585: Pretargeted radioimmunotherapy with a novel anti-oxMIF/HSG bispecific antibody and a Lu177-loaded HSG radioligand results in significant tumor regression in murine models of cancer
Authors: Schinagl Alexander , Mirkina Irina , Tarazona Alejandro Puchol 
Published: April 2023

Abstract
Background: Radioimmunotherapy (RIT) of patients with solid tumors poses a challenge due to the slow blood clearance and delayed tumor uptake of directly radiolabeled antibodies that can cause high radiation exposure to normal tissues. Pretargeting techniques utilizing bispecific antibodies (bsmAbs) overcome these limitations by administering the tumor-targeting antibody and the radioactive payload sequentially. First, the bsmAb is injected and allowed to accumulate in the tumor. Once &gt;95% bsmAbs have cleared from circulation, a small radioligand with high affinity to the bispecific antibody is administered. Due to its pharmacokinetic profile, the radioligand quickly binds to the tumor-trapped bsmAbs while excess radioligand is rapidly excreted by the kidneys. Thereby, high tumor/non-tumor ratios are achieved. Oxidized Macrophage Migration Inhibitory Factor (oxMIF) is the disease-related structural isoform of the pleiotropic cytokine MIF and is specifically present in tumor tissue. Here we show preclinical efficacy of an anti-oxMIF x anti-HSG (histamine-succinyl-glycyl) bsmAb designed for pretargeted RIT (PRIT).
Methods: Infrared dye-labeled cON-05, an anti-oxMIF x anti-HSG bsmAb, was administered to Balb/c mice bearing subcutaneous CT26 cancer syngrafts to assess tumor uptake and retention by infrared imaging and its pharmacokinetics by ELISA. A PRIT regimen using cON-05 in conjunction with a Lu177-loaded di-HSG peptide was examined in Balb/c mice bearing subcutaneous (s.c.) CT26 colon cancer syngrafts and in Balb/c nude mice bearing s.c. CFPAC-1 pancreatic cancer xenografts.
Results: Infrared dye-labeled cON-05 accumulated in the tumor and was retained for &gt;7 days. cON-05 was found to clear from circulation following a biexponential decay with only 1-2% of the injected dose remaining in plasma after 3-5 days post-injection. Significant tumor regression and survival benefit (100% cON-05 vs. 0% vehicle) were achieved in mice bearing CT26 colorectal tumors, if cON-05 (5 mg/kg) was administered 3 days prior to applying Lu177-di-HSG. In the same model, when changing the pretargeting interval to 5 days, significant tumor growth inhibition (TGI; 29% and 44% on day 9) and survival benefit (15 and &gt;21 days cON-05 vs. 9 days vehicle) could be demonstrated for 2.5 and 5 mg/kg cON-05. In a CFPAC-1 pancreatic cancer mouse xenograft model, 38% TGI on day 28 was achieved upon injection of 5 mg/kg cON-05 followed by Lu177-di-HSG 5 days later.
Conclusion: cON-05 is a novel anti-oxMIF x anti-HSG bsmAb designed for PRIT. cON-05 shows good tumor penetration and retention and tumor growth inhibition in conjunction with Lu177-di-HSG peptide in colorectal and pancreatic cancer mouse models. PRIT with cON-05 might offer new options for patients with difficult-to-treat tumors (e.g., pancreatic, gastric, head & neck)
Citation Format: Alexander Schinagl, Irina Mirkina, Alejandro Puchol Tarazona. Pretargeted radioimmunotherapy with a novel anti-oxMIF/HSG bispecific antibody and a Lu177-loaded HSG radioligand results in significant tumor regression in murine models of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 585.