Antibody-directed targeting of chemotherapeutic nanomaterials to primary human cancers could improve efficacy and reduce off-target toxicities. We developed an ex vivo model to study the targeting of primary human Chronic Lymphocytic Leukemia (CLL) in whole blood samples from 15 subjects with CLL. Anti-CD20 targeted polyethylene glycol (PEG)-based nanoparticles had generally efficient targeting of CLL cells and low off-target phagocytosis by neutrophils and monocytes. There was however substantial patient-patient variability (up to 164-fold difference in CLL targeting), driven in part by variance in pre-existing anti-PEG antibodies which reduced targeting effects. This suggests patients with lower PEG antibody levels may benefit more from targeted therapies. This was further exemplified by antibody-functionalized doxorubicin-containing PEGylated liposomes, which had relatively poor targeting of CLL in blood and high off-target uptake (significantly correlated with anti-PEG IgG levels in blood) and killing of almost all monocytes within 24 hours. Personalized low-fouling and non-PEGylated particle systems are needed to realize the potential of targeting chemotherapies. Overall, our human ex vivo model of tumor targeting by antibody-directed nanoparticles delineates limitations and opportunities of tumor-targeting nanomedicines.

The authors have declared no competing interest.

This study was supported by an Australian Research Council (ARC) Discovery Project (DP210103114 to FC, SJK, YJ), an ARC Discovery Early Career Researcher Award (DE230101542 to YJ), a Maxwell Eagle Endowment Award for Cancer Research (to YJ and SJK), an RMIT Vice-Chancellors Postdoctoral Fellowship (to YJ), an NHMRC program grant (GNT1149990 to SJK), and NHMRC Investigator grants (SJK, GNT2016732 to FC, KT).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study protocols were approved by the University of Melbourne and Royal Melbourne Hospital Human Research Ethics Committee (# 2057981.1, 13/36, 22993-34586-3) and all associated procedures were carried out in accordance with the approved guidelines.

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All data produced in the present study are available upon reasonable request to the authors