Volume 24, Issue 10, Pages (October 2016)

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Volume 24, Issue 10, Pages 1760-1770 (October 2016) Extracellular Antibody Drug Conjugates Exploiting the Proximity of Two Proteins  David J Marshall, Scott S Harried, John L Murphy, Chad A Hall, Mohammed S Shekhani, Christophe Pain, Conner A Lyons, Antonella Chillemi, Fabio Malavasi, Homer L Pearce, Jon S Thorson, James R Prudent  Molecular Therapy  Volume 24, Issue 10, Pages 1760-1770 (October 2016) DOI: 10.1038/mt.2016.119 Copyright © 2016 American Society of Gene & Cell Therapy Terms and Conditions

Figure 1 EDC parts and construction schematic. Basic components of the EDCs described in this study are: CG1 (the drug), the Linker-CG1, mAb and the EDC. CG1 was first synthesized and covalently attached to a bifunctional linker via NHS coupling to make Linker-CG1. After antibody hinge region disulfides are reduced, Linker-CG1 is added to form the EDC which was then filtered to remove unbound Linker-CG1. All steps and characterization of Linker-CG1 and its intermediates are described in detail in Supplementary Data. Molecular Therapy 2016 24, 1760-1770DOI: (10.1038/mt.2016.119) Copyright © 2016 American Society of Gene & Cell Therapy Terms and Conditions

Figure 2 Effect of linker length on EDC activity. (a) Dose response curves of A549 cells treated with EDCs constructed with the anti-dysadherin (DYS) antibody linked to CG1 via four different polyethylene glycol (PEG) linkers with 2 (green diamond), 12 (gold triangle), 24 (blue square), or 36 (red circle) repeating units spanning different lengths (27, 56, 105, 144 angstroms respectively as measured by bond distances). The figure to the right of the graph represent the 4 EDCs in order of activity from higher activity to lower activity (left to right). (b) Dose response curves of A549 cells treated with CG1 (black open circle) and 4 the different Linker-CG1s (polyethylene glycol (PEG) polymers with 2 (open green diamond), 12 (open gold triangle), 24 (open blue square), or 36 (open red circle) repeating units spanning different lengths (27, 56, 105, 144 angstroms respectively as measured by bond distances). The figure to the right of the graph represent the four Linker-CG1s in order of activity from higher activity to lower activity (left to right). Based on linker length, notice how the activities of the EDCs are reversed when compared to the Linker-CG1s. Molecular Therapy 2016 24, 1760-1770DOI: (10.1038/mt.2016.119) Copyright © 2016 American Society of Gene & Cell Therapy Terms and Conditions

Figure 3 Antibody target expression is required for EDC activity. (a) Immunofluorescence staining images of live A549, PANC-1, LOX, and H69 cells stained with antibodies specific to; dysadherin (DYS), CD147, and CD56. (b) Dose response curves for cell lines in a treated with EDC-DYS, EDC-CD147, EDC-CD56, EDC-Control P, and free CG1. Molecular Therapy 2016 24, 1760-1770DOI: (10.1038/mt.2016.119) Copyright © 2016 American Society of Gene & Cell Therapy Terms and Conditions

Figure 4 Effects of EDC on cell viability. (a) EDC-CD20. (b) EDC-CD38. Concentration sensitivity of cancer and normal cells to EDC were compared by determining the percent living cells after exposure using two different experimental protocols. Cancer cells were treated with EDC-CD20 for 72 hours and viability determined by CellTiter-Glo analysis. peripheral blood mononuclear cells were treated with EDC-CD20 for 20 hours, stained by annexin V and propidium iodide and analyzed by flow cytometry. Molecular Therapy 2016 24, 1760-1770DOI: (10.1038/mt.2016.119) Copyright © 2016 American Society of Gene & Cell Therapy Terms and Conditions

Figure 5 Mechanism of action. (a) Phase-contrast imaging of A549 cells, in the presence of the membrane impermeable nucleic acid dye Sytox-Green, treated with PBS, CG1, EDC-DYS, EDC-CD147, siRNA against ATP1A1, or nontargeting control siRNA (siNT). (b) Cell death dose response curves and EC50 values of A549 cells transfected with the indicated siRNAs and treated with CG1, EDC-DYS, or EDC-CD147. α and β refer to the subunits of the NKA. NA indicates no activity. Molecular Therapy 2016 24, 1760-1770DOI: (10.1038/mt.2016.119) Copyright © 2016 American Society of Gene & Cell Therapy Terms and Conditions

Figure 6 EDC-CD20 has dose dependent antitumor activity that surpasses Rituximab in DLBCL tumor models. Data are plotted as group mean tumor volumes post tumor implant, with standard error of the mean (SEM) which are indicated by vertical bars. (a) CB17SCID mice (n = 6 per group) bearing s.c. SU-DHL-4 xenograft tumors of an average size of 250 mm3 were treated with vehicle (dashed line) EDC-CD20 (circle) or Rituximab (diamond) at 5 mg/kg using the dosing schedule of q6dx2 via i.p. injection. (b) CB17SCID mice (n = 6 per group) bearing s.c. SU-DHL-4 xenograft tumors of an average size of 250 mm3 were treated with either vehicle (dashed line) or EDC-CD20 dosed at 0.5 mg/kg (triangle), 1.5 mg/kg (square), or 5 mg/kg (circle) using the dosing schedule of q6dx2 via i.p. injection. Molecular Therapy 2016 24, 1760-1770DOI: (10.1038/mt.2016.119) Copyright © 2016 American Society of Gene & Cell Therapy Terms and Conditions