Editors' ChoiceCancer

Aiming the magic bullet

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Science Translational Medicine  18 Nov 2020:
Vol. 12, Issue 570, eabf4686
DOI: 10.1126/scitranslmed.abf4686

Abstract

Coadministration of antibody-drug conjugates with the parent antibody improves delivery to solid tumor beds.

Antibody-drug conjugates are a promising class of anticancer drugs that combine the antigen specificity of an antibody with a cytotoxic drug. Although these drugs are being tested in hundreds of registered clinical trials, they often have a narrow therapeutic window and may not fully penetrate solid tumors. Previous studies in mice have suggested that coadministration of the unconjugated parent antibody with an antibody-drug conjugate could improve penetration of the cytotoxic drug beyond the perivascular region to better treat solid tumors.

To understand whether this approach would work in humans, Lu et al. administered an antibody-dye conjugate model to human participants who were undergoing surgery for head and neck squamous cell carcinoma. A few days before surgery, investigators gave the antibody-dye conjugate to all participants and a loading dose of the same antibody without dye to half of the participants. They then performed extensive characterization, including macroscopic and microscopic imaging of the resected tumors. The authors demonstrated that coadministration of the antibody-dye conjugate with additional non-labeled antibody improved the distribution of the antibody-dye conjugate within tumors while decreasing the uptake in healthy tissues. This approach essentially overcomes a “binding site barrier” in tumor beds as the antibodies bind their targets faster than they diffuse.

This proof-of-concept study suggests that antibody-drug conjugate dosing may be further refined to deliver cytotoxic payload throughout solid tumor beds. This approach may have broad implications for any antibody-based drug that is delivered below doses that saturate target receptors. As a result of this and similar studies, researchers are now closer to the “magic bullet” of chemotherapy that can fully penetrate solid tumors with less uptake in healthy tissues. Although the results of this study are promising, it used an antibody-dye conjugate rather than an active drug conjugate. Further studies will be needed to define the clinical effectiveness of this drug delivery strategy.

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