Efficacy of MMP9 inhibition in an orthotopic xenograft model of CRC.

<p>Tumors in the HCT116 model were allowed to reach a volume of 70–100 mm³ before treatment with a control IgG or with antibodies targeting mouse MMP9 (AB0046; anti-MMP9 [m]), human MMP9 (AB0041; anti-MMP9 [h]), or both (anti-MMP9 [m+h]). Each antibody was dosed twice a week at 15 mg/kg, whether singly or in combination, and study groups containing AB0046 received a loading dose of 50 mg/kg on the day prior to initiation of treatment. Three separate studies are shown; Study 3 (panels A, D, G); Study 2 (panels B, E, H), and Study 1 (panels C, F, I). (A-C) Change in tumor growth: (A) Study 3, (B) Study 2, (C) Study 1. For a given mouse, raw tumor volume measurements (by caliper) were normalized to the corresponding initial tumor volume (prior to the start of treatment initiation). Normalized volumes for individual mice were then averaged for each timepoint;plots show group mean +/- SEM; standard error of the mean. Significance was assessed by Kruskal-Wallis analysis (A, B) or by Mann-Whitney analysis (C). Treatment was initiated 16 days after surgical implantation of tumor fragments for Studies 1 and 3, and 17 days after implantation for Study 2. The last measurement of tumor volume was 35 days post-implantation for Study 3, 34 days post-implantation for Study 2, and 44 days post-implantation for Study 1. (D-F) Final tumor weight: (D) Study 3, (E) Study 2, (F) Study 1. Plots show mean tumor weight +/- SEM. Significance was assessed by Kruskal-Wallis analysis (D,E) or by Mann-Whitney analysis (F). Mice were terminated at 20 days (Study 3), 18 days (Study 2), or 32 days (Study 1) after treatment initiation, which corresponds to 36 days (Study 3), 35 days (Study 2), or 48 days (Study 1) after tumor implantation. (G-I) Studies 1–3; metastases incidence at study termination: (G) Study 3, (H) Study 2, (I) Study 1. Metastases were scored as present or absent, based on open-imaging visualization of the GFP-labeled HCT116 tumor cells at areas distal to the primary tumor mass. Plots show the percentage of mice displaying metastases per group. Significance was assessed by Fisher’s exact test. For all panels in Fig 7, P value designations are as follows: * < 0.05, ** < 0.01, *** <0.001, **** < 0.0001.