Afuco™ Anti-Human HGF ADCC Recombinant Antibody (TAK-701), ADCC Enhanced (CAT#: AFC-335CL)

Figure 1 Compound 1 enhances the efficacy of an HGF-neutralizing antibody. Mice with KP4 pancreatic xenografts (A) or U-87MG glioblastoma xenografts (B) were treated with the indicated regimens (n = 6 or 10 mice per group, respectively, for KP4 or U-87MG xenografts).

Tumor volumes (mean ± SEM) were measured over time. Significance of single-agent treatments versus vehicle control KP4 tumors was determined using one-way ANOVA with Dunnett test (*, P < 0 .025), and significance of single agents versus combination was determined using the Wilcoxon test (⁁, P < 0.05). Tumor outgrowth after treatment cessation was monitored in the U-87MG model, and the Log-rank test was used to determine statistical significance in TTE between treatment groups and vehicle control group (*, P < 0.05; **, P < 0.01; and ***, P < 0.001).

Farrell, P. J., Matuszkiewicz, J., Balakrishna, D., Pandya, S., Hixon, M. S., Kamran, R., ... & Mizutani, A. (2017). MET tyrosine kinase inhibition enhances the antitumor efficacy of an HGF antibody. Molecular cancer therapeutics, 16(7), 1269-1278.

Figure 2 Combination synergy correlates with sustained suppression of MET phosphorylation, reduction of MET protein levels, and reduction of 4E-BP1 phosphorylation.

Mice bearing U-87MG xenografts (n = 10 mice per group) were treated with the indicated regimen (A, right). MET TKIs were administered daily via oral gavage, and TAK-701 was administered weekly via i.v. route. Tumor volumes (mean ± SEM) were measured over time. Statistical differences in TTE vs. vehicle group were calculated using the Log-rank test. See Supplementary Fig. S3 for the Kaplan–Meier survival plot. Two separate cohorts of mice were sacrificed for the pathway biomarker analysis, one on day 5 at 2 hours after dose and the other on day 5 at 24 hours after dose (n = 3 mice per group for each group: 100 mg/kg Compound 1, 10 mg/kg TAK-701, and 100 mg/kg Compound 1 + 10 mg/kg TAK-701). Phosphorylated MET and total MET were evaluated by immunoassay (A, left) and ERK, and PI3K/AKT pathway markers were evaluated by Western blot (B).

Farrell, P. J., Matuszkiewicz, J., Balakrishna, D., Pandya, S., Hixon, M. S., Kamran, R., ... & Mizutani, A. (2017). MET tyrosine kinase inhibition enhances the antitumor efficacy of an HGF antibody. Molecular cancer therapeutics, 16(7), 1269-1278.

Figure 3 Effects of the combination of gefitinib and either TAK-701 or PHA-665752 on cell signaling in gefitinib-resistant NSCLC cells.

HCC827 cells, HCC827 GR5 cells, or HCC827-HGF2 cells were incubated for 6 h in medium containing 10% serum in the absence or presence of gefitinib (1 μM), PHA-665752 (500 nM), or TAK-701 (50 μg/mL), as indicated. Cell lysates were then prepared and subjected to immunoblot analysis with antibodies to phosphorylated or total forms of EGFR, MET, AKT, or ERK or with those to β-actin.

Okamoto, W., Okamoto, I., Tanaka, K., Hatashita, E., Yamada, Y., Kuwata, K., ... & Janne, P. A. (2010). TAK-701, a humanized monoclonal antibody to HGF, reverses gefitinib resistance induced by tumor-derived HGF in non-small cell lung cancer with an EGFR mutation. Molecular Cancer Therapeutics, molcanther-0481.

Figure 4 Effects of the combination of TAK-701 and gefitinib on the growth of gefitinib-resistant NSCLC cells in vivo.

Nude mice with tumor xenografts established by subcutaneous injection of HCC827-Mock (A) or HCC827-HGF2 (B) cells were treated for 7 weeks with vehicle (control), gefitinib (50 mg/kg), TAK-701 (5 mg/kg), or both drugs, as described in Materials and Methods. Tumor volume was determined at the indicated times after the onset of treatment. Data are means ± SEM from five mice per group.

Okamoto, W., Okamoto, I., Tanaka, K., Hatashita, E., Yamada, Y., Kuwata, K., ... & Janne, P. A. (2010). TAK-701, a humanized monoclonal antibody to HGF, reverses gefitinib resistance induced by tumor-derived HGF in non-small cell lung cancer with an EGFR mutation. Molecular Cancer Therapeutics, molcanther-0481.

Figure 5 Effects of the combination of TAK-701 and gefitinib on the growth of gefitinib-resistant NSCLC cells in vivo.

Nude mice with tumor xenografts established by subcutaneous injection of HCC827-Mock (A) or HCC827-HGF2 (B) cells were treated for 7 weeks with vehicle (control), gefitinib (50 mg/kg), TAK-701 (5 mg/kg), or both drugs, as described in Materials and Methods. Tumor volume was determined at the indicated times after the onset of treatment. Data are means ± SEM from five mice per group.

Okamoto, W., Okamoto, I., Tanaka, K., Hatashita, E., Yamada, Y., Kuwata, K., ... & Janne, P. A. (2010). TAK-701, a humanized monoclonal antibody to HGF, reverses gefitinib resistance induced by tumor-derived HGF in non-small cell lung cancer with an EGFR mutation. Molecular Cancer Therapeutics, molcanther-0481.