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. 2022 Jul 5;13:3869. doi: 10.1038/s41467-022-31601-z

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© The Author(s) 2022, corrected publication 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — a IC₅₀ of cisplatin, paclitaxel and MMAE in human and murine cancer cell lines by Alamar Blue assay. Scatter plot with mean of biological replicates, number of biological replicates are provided in the Source Data file. b Heatmap depicting differential gene expression of control (n = 2) and MMAE (n = 3)-treated B16 cells. RNA expression analyzed using NanoString PanCancer IO 360 Panel. c Schema of antibody and cell penetrating peptide conjugates of MMAE using MC-VC-PABC linkers. d Structural representation of Cy5-labeled ADC with 4 MMAE molecules and 1 Cy5 per antibody. e HER3 expression in cancer cell lines. Immunoblot for total HER3 and GAPDH. f Cy5 localization of CDX3379-MMAE in subcutaneous tumor xenografts (yellow circles indicate tumor locations). 2.5 nmoles of Cy5-labeled CDX3379-MMAE or saline vehicle injected and whole mouse imaged for Cy5 (white signal) at 48 h. Gut auto-fluorescence indicated by blue arrows. Tissue sections containing tumor and adjacent normal muscle stained for CK5 (green) and imaged for Cy5 (red). Tumor (T) and normal muscle (M) boundary (yellow dotted line) delineated by CK5, scale bar = 100 μm. g Spatial localization of CDX3379-MMAE in subcutaneous syngeneic tumors. 2.5 nmoles of Cy5-labeled ADC or saline vehicle injected into tumor bearing mice and imaged at 48 h. For MOC1 tumors (yellow circles indicate tumor locations), whole mouse imaged for Cy5 (white signal). Imaged whole mouse delineated by dashed gray line. For LL/2 and MOC2 tumors, tumors resected (yellow dashed lines) and imaged for Cy5 (orange signal), scale bar = 5 mm. h Structural representation of ACPP-MMAE drug conjugate. MMP 2/9 cleavage site indicated by dashed red line. i Gelatin zymography of syngeneic murine tumor and adjacent muscle tissues. MMP-2 and MMP-9 standard activity in far-left lanes. j Structural representation of ratiometric ACPP probe with Cy5 and Cy7 attached to the polypeptide ends of ACPP. k Mice with subcutaneous LL/2 tumors (yellow circles indicate tumor locations) injected with 10 nmoles ratiometric ACPP or water vehicle. In situ whole mouse Cy5 and Cy7 imaging with Cy5:Cy7 emission ratio calculated (pseudocolor scale bar shown). Harvested tissues Cy5 imaging (white signal) shown and mean Cy5:Cy7 ratio scatter plot, n = 2 tissues. Images in (e, i) representative of three independent experiments. Source data provided in Source Data file.