# Clinical development of a DLL3-targeted theranostic for small cell lung cancer

> **NIH NIH U01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $335,437

## Abstract

PROJECT SUMMARY
 Small cell lung cancer (SCLC) is remarkable for exceptionally high metastatic potential, initial robust
response to DNA damaging agents, and near universal development of resistance. This combination of
predilection for early metastasis acquired treatment resistance – often times manifested as cross resistance to
multiple agents – highlights a critical need for novel systemic therapies operating through a novel mechanism
in order to achieve improved patient outcomes.
 Delta-like ligand 3 (DLL3), has recently been identified as a therapeutic target in SCLC. The highly
tumor-selective surface expression of this protein make it an excellent candidate target for an antibody drug
conjugate (ADC). Rovalpituzumab tesserine (Rova-T) is one such ADC that is showing encouraging efficacy
signals in the clinic. However, despite apparent clinical benefit, this agent has also been associated with some
severe adverse events attributable to the presence of the anthracycline PBD warhead. DLL3 targeting
approaches are in need of both a real-time, quantitative diagnostic biomarker and a therapeutic approach with
reduced toxicity.
 We propose a theranostic approach comprising on 89Zr immunoPET and a 90Y/177Lu
radioimmunotherapeutic. The first Aim improves upon already promising bioconjugation chemistry. We are
already able to obtain high-contrast immunoPET images using non-specific amine labeling and site-specific
maleimide bioconjugation. We will improve upon this approach by developing more stable thiol-clickable
methylsuflone chelators for 89Zr and 90Y/177Lu to minimize kidney dose. The second Aim identifies preclinical
dosing parameters and comprehensively optimizes efficacy and toxicity in a traditional cell line xenograft. Our
preliminary imaging data is focused on H82, an SCLC cell lined derived from a chemoexperienced patient. This
cell line is very resistant to etoposide in vitro and in vivo and will be used to identify a radiotherapy dose that
demonstrates efficacy in vivo, while minimizing dose to the kidney. Different dose ranges and schedules will be
explored. The final Aim explores radiotherapy in a variety of in vivo contexts including lesion sizes ranging from
0.1 to 10 mm in diameter and representing both chemonaïve and chemoresistant disease. Radioisotopes have
different energy deposition depending on the volume of the tumor being targeted. We will evaluate 90Y and
177Lu radioisotopes in different in vivo models of small cell lung cancer for the ability to eradicate lesions of
different sizes. A unique resource in the lab is our collection of 10 paired chemonaïve and chemoresistant
patient-derived xenograft lines. We will place particular emphasis on establishing efficacy in the context of
acquired chemoresistance.
 Data obtained in this study should provide preclinical evidence in support of clinical translation of a
DLL3 targeting theranostic based on rovalpituzumab.

## Key facts

- **NIH application ID:** 10172863
- **Project number:** 5U01CA213359-05
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** John Thomas Poirier
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $335,437
- **Award type:** 5
- **Project period:** 2017-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10172863

## Citation

> US National Institutes of Health, RePORTER application 10172863, Clinical development of a DLL3-targeted theranostic for small cell lung cancer (5U01CA213359-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10172863. Licensed CC0.

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