Article Text

Download PDFPDF

1156 Improved anti-ovarian cancer effectiveness of HER2-directing ADC via engineering with a super-hydrophilic PMPC polymer
  1. Jie Ren,
  2. Chloe E Jepson,
  3. Stella U Azolibe,
  4. Charles J Kuhlmann,
  5. Madison T Blucas,
  6. Yoshiko N Kamata and
  7. Masakazu Kamata
  1. University of Alabama at Birmingham, Birmingham, AL, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Antibody-drug conjugates (ADC) are composed of a tumor-targeting antibody and a cytotoxic payload, enabling the specific elimination of targeted cells. Ado-trastuzumab emtansine (T-DM1) was approved in 2013 as an ADC directing human epidermal growth factor receptor 2 (HER2) and has been widely used for the treatment of HER2+ breast cancer. However, its potency was moderate against other cancers expressing HER2+, such as ovarian cancer having a refractory and metastatic nature due to the limited drug-to-antibody ratio (DAR) of 2–4. Using a higher DAR improves T-DM1’s cytotoxicity, but results in poor pharmacokinetics and tumor targeting, increasing off-target toxicity and compromising tumor elimination. We hypothesize that site-specific conjugation of a super-hydrophilic polymer, poly (2-Methacryloyloxyethyl phosphorylcholine) (PMPC) allows a higher DAR without compromising its biological functions.

Methods PMPC was conjugated to trastuzumab (Tmab) thiol residues through a peptide crosslinker that is sensitive to the tumor-enriched matrix metalloproteinases (MMP-2 and 9). Emtansine (DM1) was subsequently conjugated to the lysine groups of Tmab with average DAR of 8.6 (T-DM1PMPC-MMP). The cellular binding, uptake, and HER2-specific cytotoxicity were tested in the SKOV3 human OC cell line. The pharmacokinetics, in-vivo tumor targeting, toxicity, and therapeutic outcome were validated in SKOV-3 xenograft NOD.Cg-Prkdcscid_Il2rg_tm1Wjl/SzJ (NSG) mice in comparison with T-DM1 carrying standard DAR (3.6) and high DAR (8.6).

Results PMPC conjugation endowed functional stability to T-DM1 with high DAR (~10). The cellular uptake and cytotoxicity were reduced by PMPC conjugation but retrieved after MMP-mediated PMPC detachment in the tumor microenvironment. T-DM1PMPC-MMP displayed prolonged body circulation, enhanced tumor-specific delivery, and reduced off-target toxicity compared with T-DM1(8.6) in xenograft mice. Two doses (8 mg/kg) of T-DM1PMPC-MMP achieved complete elimination of tumors with a size >200 mm3 without relapse, whereas tumors rebounded 3 weeks after treatment with T-DM1(3.6).

Conclusions This novel methodology that addresses the current issue of T-DM1 with high DAR has great potential for the targeting therapy of refractory OC and may be used for other HER2+ aggressive cancers.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.