# Non-invasive Quantification of Dose-Exposure-Response of PD-L1 Therapeutics at the Tumor

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $457,540

## Abstract

Project Summary.
Completeness of drug-target engagement and appropriately addressing cellular heterogeneity are critical for the
success of anti-cancer therapeutics. Immune checkpoint therapeutics are no exception, for it is poorly
understood why the majority of patients (70%) do not respond. Current immune checkpoint therapy patient
stratification (tumor immunohistochemistry) makes projection of results highly unpredictable for determining
suitable candidacy of individual patients. Total PD-L1 target levels and their engagement by therapeutic
antibodies (mAbs) at the tumor are crucial for biological activity. However, technology to non-invasively measure
these levels is unavailable. We propose a novel method that can be used to predict efficacy at every identifiable
tumor by measuring target expression levels and drug-target engagement in real-time. We will perform these
studies to evaluate binding of therapeutic mAbs to programmed death ligand-1 (PD-L1), an immune checkpoint
protein that forms the backbone of therapeutic efforts in immuno-oncology today. All the approved PD-L1
therapeutics are mAbs. mAb therapeutics pose unique challenges to pharmacodynamics measurements due to
their size and limited penetration into tumors. T cell-based pharmacodynamic measurements from peripheral
blood are used in dose-finding of immune checkpoint therapeutics. However, lesion occupancy levels have not
been calculated in vivo using mAbs, in part due to their prolonged circulation time, which could be addressed by
using a peptide instead. Moreover, tumor concentrations of mAbs are significantly influenced by dynamic
changes in target expression, as well as parameters intrinsic to tumor, such as interstitial pressure, and extrinsic
parameters related to their complex PK. These findings underscore the need to develop non-invasive tools to
assess total PD-L1 levels, delivery, retention and engagement of PD-L1 mAbs at all identifiable lesions. Positron
emission tomography (PET) is increasingly used to guide cancer immunotherapy. Precision PET radiotracers
can provide dynamic in vivo assessment of PD-L1 expression, and can improve responses and outcomes of
these therapies. However, they have not been used for the evaluation of PD-L1 therapeutics. We recently
developed a high-affinity human PD-L1-specific PET imaging peptide that provides high image contrast to guide
immune checkpoint therapy. The goals of this proposal are to establish our PD-L1 PET tracer performance to
measure total tumor PD-L1 levels, evaluate drug delivery and PD-L1 engagement at the tumor by different mAbs,
and determine dose-exposure-response of mAbs to enhance and accelerate immune checkpoint therapy
management. This new technology enables provision of an empirical means to determine who will benefit from
immune checkpoint therapy, aid/enable/advance dose selection and optimization, assist drug development and
evaluation, and identification of off-target liabilities to reduce adverse effects...

## Key facts

- **NIH application ID:** 10197853
- **Project number:** 5R01CA236616-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Sridhar Nimmagadda
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $457,540
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197853

## Citation

> US National Institutes of Health, RePORTER application 10197853, Non-invasive Quantification of Dose-Exposure-Response of PD-L1 Therapeutics at the Tumor (5R01CA236616-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10197853. Licensed CC0.

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