# Novel antibody-drug conjugates targeting T-cell lymphoma

> **NIH NIH R43** · ASYLIA THERAPEUTICS, INC. · 2022 · $246,451

## Abstract

Abstract: T-cell lymphomas have remained treatment-challenging, not least because of their remarkable
heterogeneity. The lab of Robert Orlovsky (co-founder of Asylia) analyzed the membrane proteome of peripheral
and cutaneous T-cell lymphoma and discovered that surface Heat shock protein (csHSP)-70 as being
consistently overexpressed. While HSP70 is well established as an intracellular stress-response chaperone, its
localization to the cell surface in cancer, is gaining increased attention. Considering the recent clinical successes
of antibody-drug conjugates and the exceptionally high and selective overexpression of cell surface HSP70 in
T-cell lymphoma, we summarize that csHSP70 presents as an exceptionally attractive target for antibody drug
conjugates (ADC) for the treatment of this malignancy. We have generated a high affinity monoclonal antibody
(clone 239-87) specifically recognizing cell-surface HSP70. In preliminary data, we have generated an ADC of
mAb 239-87 with MMAE, which specifically bound csHSP70 on T-cell NHL cell lines but did not bind normal
peripheral blood-derived cells. Linked to MMAE, the 239-87-MMAE ADC showed cytotoxic activity against both
peripheral and cutaneous T-cell lymphoma lines cell lines with comparable, or greater potency than the leading
clinical ADC, brentuximab vedotin.
 We now propose a series of critical experiments to accelerate the clinical translation of 239-87 ADCs for
the treatment of T-cell lymphoma. In aim 1, we will humanize mAb 239-87 and optimize the drug-like
characteristics of the current murine clone. We will study binding of the leads to soluble HSP70, and to csHSP70
in wild-type and genome edited cell models to verify that they retain csHSP70 affinity and specificity. In specific
aim 2, we will convert clone 239-87 mAb into an ADC. We will first synthesize a panel of ADCs based on the
optimal lead antibody molecule linked to MMAE, a maytansine, a camptothecin, and a pyrrolobenzodiazepine
with cathepsin- and acid-cleavable linkers and compare their efficacy against T-cell lymphoma cell lines. Next,
we will genetically modulate csHSP70 and perform internalization and quantitative flow studies to determine the
minimum csHSP70 expression needed to see anti-cancer efficacy. Finally, we will verify the potential for synergy
between our ADCs and agents that enhance csHSP70, such as histione deacetylase inhibitors. In Aim 3, we will
validate the activity of clone 239-87 ADCs using in vivo tumor cell line-derived models. Next, we will validate the
activity of selected best performers in more physiologically relevant patient-derived xenograft (PDX) models.
Finally, we will perform pharmacokinetic studies in these PDXs to begin to understand potential drug distribution
and toxicity parameters.
 Taken together, these studies will provide a proof-of-concept that HSP70-targeted ADCs have the
necessary efficacy and pharmacologic properties for development as attractive drug candidates and allow us to
move ...

## Key facts

- **NIH application ID:** 10386723
- **Project number:** 1R43CA268668-01
- **Recipient organization:** ASYLIA THERAPEUTICS, INC.
- **Principal Investigator:** John P. Miller
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $246,451
- **Award type:** 1
- **Project period:** 2022-04-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10386723

## Citation

> US National Institutes of Health, RePORTER application 10386723, Novel antibody-drug conjugates targeting T-cell lymphoma (1R43CA268668-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10386723. Licensed CC0.

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