Antigen-specific radiosensitization

Sloan-Kettering Inst Can Research, New York NY

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT: A total of 13 antibody drug conjugates (ADCs) are now FDA approved, including several in solid tumors. In this application, we propose that the ADC format can deliver potent radiosensitizers that are specifically targeted to antigen-bearing tumor cells with relative sparing of normal tissue and thereby improve the therapeutic index of radiosensitizion. We have developed first-in-class ADCs and payloads that are specifically designed for combination with external beam radiotherapy. The first molecules are HER2-directed ADCs containing DNA damage response inhibitors as payloads and have demonstrated efficacy in vitro and in vivo with potencies competitive with clinically relevant benchmarks. Other HER2-directed ADCs have established clinical efficacy in breast adenocarcinomas, non-small cell lung cancers, colorectal cancers, and gastroesophageal/gastric cancers. In one version, the payload is a small molecule inhibitor of the ATM kinase, which is a sensor of double strand breaks and activates DNA damage-induced cell cycle checkpoints, phosphorylates key double strand break repair genes, and provides resistance to radiotherapy and other DNA damaging agents. In a second and parallel effort we have developed the most potent known inhibitor of the nonhomologous end- joining factor Ligase IV (LIG4) with efficacy at 10nM. Our design employs small double stranded DNA oligos with a strategically placed E3 ubiquitin ligase ligand pomalidolide to induced ubiquitination and degradation of LIG4. This LIG4 degrader (NHEJ-P) is highly radiosensitizing and ideal for conjugation as an antibody-oligo- conjugate, which have also emerged clinically. In this proposal, we seek to further develop these lead ADC and AOC molecules in three independent specific aims. In SA1, we will further develop the in vivo activity of the trastuzumab-ATMi ADC (named t-ATMi) in terms of the onset and duration of ATM inhibition and test in additional xenograft models commonly used anti-HER ADC development. In SA2, we will perform lead optimization of our LIG4 degrader payload (NHEJ-P), evaluate its mechanism of action, and test antibody- oligo-conjugate formulations in vitro and in vivo. In SA3, we will pursue thorough investigations into possible overlapping toxicities between ADC/AOCs and radiation including both on-target/off-tumor and off-target toxicities from the side of the ADC/AOC and acute, subacute, and late radiation toxicities to the skin, liver, kidney bowel, lung, and heart, respectively. We have assembled a team with broad expertise in medicinal chemistry, DNA repair, ADC development, and radiation toxicity modeling in mice to support each aim and subaim. The net result of this project will be to de-risk and refine radiosensitizing ADC and AOCs ahead of clinical translation. The impact of this project may extend beyond HER2+ malignancies and even beyond radiotherapy, since an effectively linker-payload could be conjugated to other clinically active antibodies and combined with other DNA damaging systemic therapies.