Data from Bispecific Antibody to ErbB2 Overcomes Trastuzumab Resistance through Comprehensive Blockade of ErbB2 Heterodimerization
Bohua LiYanchun MengLei ZhengXunmin ZhangQing TongWenlong TanShi HuHui LiYang ChenJinjing SongGe ZhangLei ZhaoDapeng ZhangSheng HouWeizhu QianYajun Guo
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<div>Abstract<p>The anti-ErbB2 antibody trastuzumab has shown significant clinical benefits in metastatic breast cancer. However, resistance to trastuzumab is common. Heterodimerization between ErbB2 and other ErbBs may redundantly trigger cell proliferation signals and confer trastuzumab resistance. Here, we developed a bispecific anti-ErbB2 antibody using trastuzumab and pertuzumab, another ErbB2-specific humanized antibody that binds to a distinct epitope from trastuzumab. This bispecific antibody, denoted as TP<sub>L</sub>, retained the full binding activities of both parental antibodies and exhibited pharmacokinetic properties similar to those of a conventional immunoglobulin G molecule. Unexpectedly, TP<sub>L</sub> showed superior ErbB2 heterodimerization-blocking activity over the combination of both parental monoclonal antibodies, possibly through steric hindrance and/or inducing ErbB2 conformational change. Further data indicated that TP<sub>L</sub> potently abrogated ErbB2 signaling in trastuzumab-resistant breast cancer cell lines. In addition, we showed that TP<sub>L</sub> was far more effective than trastuzumab plus pertuzumab in inhibiting the growth of trastuzumab-resistant breast cancer cell lines, both <i>in vitro</i> and <i>in vivo</i>. Importantly, TP<sub>L</sub> treatment eradicated established trastuzumab-resistant tumors in tumor-bearing nude mice. Our results suggest that trastuzumab-resistant breast tumors remain dependent on ErbB2 signaling and that comprehensive blockade of ErbB2 heterodimerization may be an effective therapeutic avenue. The unique potential of TP<sub>L</sub> to overcome trastuzumab resistance warrants its consideration as a promising treatment in the clinic. <i>Cancer Res; 73(21); 6471–83. ©2013 AACR</i>.</p></div>Keywords:
Pertuzumab
Growth inhibition
Humanized antibody
<p>Supplementary Figure 3 shows how trastuzumab plus pertuzumab, but not trastuzumab alone, overcome NRG1 enhanced pro-survival signaling in HER2-positive breast cancer cells and in ex vivo tumors.</p>
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Abstract Objective: Gastric cancer has a poor prognosis. HER2 targeting therapy for gastric cancer would be considered important, because HER2 protein in gastric cancer is reported to be prognosis factor as well as breast cancer. Recently, trastuzumab has provided benefits for patients with HER2-positive gastric cancer in the ToGA trial (a phase III study of trastuzumab in HER2-positive advanced gastric cancer). On the other hand, pertuzumab, a new anti-HER2 antibody, can bind a different HER2 domain from trastuzumab and inhibits tumors by preventing the dimerization of HER2 and other HER family proteins. In this study, we investigated the efficacy of pertuzumab in combination with trastuzumab to consider a new approach to HER2-positive gastric cancers. Results: We examined the anti-tumor activity of pertuzumab in combination with trastuzumab in the mouse xenograft models of HER2-positive human gastric cancer, NCI-N87 and 4-1ST. Pertuzumab and trastuzumab were administered once a week i.p. for 3 weeks. The combination group showed a significant anti-tumor activity (tumor growth inhibition (TGI) % = 145 % and 105 % in NCI-N87 and 4-1ST, respectively) compared with the group treated only with pertuzumab (TGI % = 31 % and 29 %) or that treated only with trastuzumab (TGI % = 52 % and 55 %). In addition, the anti-tumor activity was higher than the maximum anti-tumor activities in either of those monotherapy groups. Furthermore this combination effect was also observed in vitro. Phosphorylation of HER2 was strongly blocked by exposure of these antimodies in combination. EGF-stimulated phosphorylation of EGFR was also down-regulated. As other mechanisms of the combination effect, we examined the ADCC activity of pertuzumab and trastuzumab by means of a real-time cell analyzer. Pertuzumab and trastuzumab had ADCC activity and that activity was enhanced when both of them were exposed. In addition we examined micro-vessel density (MVD) change after treatment in NCI-N87 tumor tissues with CD31-immunostaining. We observed MVD inhibition only in the tumor tissues treated with both pertuzumab and trastuzumab and not in the tissues treated with the drugs separately. VEGF levels in tumor tissues were reduced by pertuzumab or trastuzumab. The present results suggest that pertuzumab in combination with trastuzumab shows significant anti-tumor activity in HER2-positive human gastric cancers not only by directly inhibiting cell growth through down-regulation of HER2/EGFR signaling but also by enhancing ADCC activity and reducing MVD. Conclusion: The anti-tumor activity of pertuzumab and trastuzumab was higher than the maximum anti-tumor activity showed when pertuzumab or trastuzumab were used as single agent. The present study suggests that this combination therapy may provide greater benefits for patients with HER2-positive gastric cancers. Clinical evaluation is expected. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3477.
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Human epidermal growth factor receptor (HER) 2 (HER2) is overexpressed in 20–30% of breast cancers. HER2 is a preferred target for treating HER2-positive breast cancer. Trastuzumab and pertuzumab are two HER2-targeted monoclonal antibodies approved by the Food and Drug Administration (FDA) to use as adjuvant therapy in combination with docetaxel to treat metastatic HER2-positive breast cancer. Adding the monoclonal antibodies to treatment regimen has changed the paradigm for treatment of HER2-positive breast cancer. Despite improving outcomes, the percentage of the patients who benefit from the treatment is still low. Continued research and development of novel agents and strategies of drug combinations is needed. A thorough understanding of the molecular mechanisms underlying the action and synergism of trastuzumab and pertuzumab is essential for moving forward to achieve high efficacy in treating HER2-positive breast cancer. This review examined and analyzed findings and hypotheses regarding the action and synergism of trastuzumab and pertuzumab and proposed a model of synergism based on available information.
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B102 The humanized monoclonal antibody (mab) trastuzumab, which specifically binds to the extra-cellular domain of HER2 has become standard of care for patients with HER2-positive breast cancer. Unfortunately, some patients progress while on trastuzumab and chemotherapy combination treatment. One way to avoid progression is to block HER pathways more completely by targeting other HER-family growth factor receptors like HER1/EGFR or HER3. We investigated whether HER2-positive tumours progressing under trastuzumab therapy can be inhibited by the combination of trastuzumab in multiple lines with other HER-family receptor targeting agents (pertuzumab and lapatinib) that are in clinical development, and together with clinically established cytotoxic drugs (paclitaxel and 5-FU). Since up-regulation of VEGF has been suggested to promote tumour progression, we also tested the combination of trastuzumab with the anti-huVEGF targeting mab bevacizumab. We used the HER2-positive human breast cancer xenograft model KPL-4 which is known to shed the extra-cellular domain of HER2 and to co-express HER1 and HER3.
Mice carrying well established KPL-4 xenograft tumours of about 100-120 mm 3 size were treated once weekly (q7d) with 15mg/kg i.p. trastuzumab, following an initial 2-fold loading dose. After 2 weeks of trastuzumab treatment, those mice with progressively growing tumours of about 160-250 mm 3 in size were randomly distributed into various groups in order to test different treatment options. The compounds used for second line treatment included: (1) pertuzumab (15mg/kg, i.p. q7d), a novel HER dimerisation inhibitor; (2), bevacizumab (5mg/kg, q3d, i.p.) which inactivates huVEGF-A; (3) lapatinib (25mg/kg, 2qd, p.o.), which is described as a dual HER1 and HER2 tyrosine kinase inhibitor, and two cytotoxic drugs, (4) paclitaxel (15mg/kg, q7d, i.v.) and (5) 5-FU (50mg/kg, q7d, i.v.).
While trastuzumab treatment was continued after progression, the addition of either pertuzumab or bevacizumab for combined second line treatment demonstrated significant antitumour activity compared to untreated or trastuzumab single agent controls. Adding paclitaxel or 5-FU on top of the dual antibody combinations was clearly superior, resulting in complete tumour remissions and long term survival. In contrast, various combinations of trastuzumab with lapatinib were not efficacious and less well tolerated, especially with the addition of paclitaxel or 5-FU.
In summary, our data indicate that there are several effective treatment options for HER2 positive tumours to be used for treatment in multiple lines of trastuzumab with monoclonal antibodies targeting HER-family receptors and/or angiogenesis. The addition to continued trastuzumab therapy of either the HER dimerisation inhibitor pertuzumab or the anti-VEGF mab bevacizumab together with cytotoxic drugs, resulted in superior antitumour activity with complete tumour remission and long term survival, compared to lapatinib-based combinations.
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The majority of patients with metastatic breast cancer who are treated with the anti-HER2 monoclonal antibody, trastuzumab, generally develop resistance to the drug within a year after initiation of the treatment. Here we describe a new anti-HER2 humanized monoclonal antibody, 19H6-Hu, which binds to HER2 extracellular domain (ECD) with high affinity and inhibits proliferation of multiple HER2-overexpressing cancer cell lines as a single agent or in combination with trastuzumab. 19H6-Hu binds to the domain III in proximity to the domain IV of HER2 ECD, which differs from trastuzumab and pertuzumab. 19H6-Hu in combination with trastuzumab was more effective at blocking phosphorylation of ERK1/2, AKT(S473)and HER2 (Y1248) in HER2-positive cancer cells compared to trastuzumab alone or in combination with pertuzumab. Combination of three antibodies, 19H6-Hu, inetetamab (a trastuzumab analog) and pertuzumab exhibited much stronger inhibition of large NCI-N87 tumor xenografts (>400mm3) than the current standard of care, inetetamab (trastuzumab) plus Docetaxel (DTX), as well as the combination of 19H6-Hu, inetetamab and DTX. Our results highlight the functional variability of HER2 domains and provide a new insight into the design of HER2-targeting agents.
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Pertuzumab, a humanized antibody drug, has improved outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, when administered in combination with trastuzumab and other chemotherapies. Cardiotoxicity due to trastuzumab is widely recognized, while data on pertuzumab-based treatments in daily clinical practice are lacking. We herein report 2 Japanese patients, aged 72 and 49 years, who developed left ventricular dysfunction after pertuzumab administration, following long-term trastuzumab treatments. Both patients underwent curative surgery for their HER2-positive breast cancer and received anthracycline-based treatments. After developing metastatic disease, trastuzumab-based treatments were administered without cardiac toxicity, but both patients developed left ventricular dysfunction after pertuzumab administration (6 and 13 cycles, respectively). Although several large randomized trials have shown no additive effect of pertuzumab on cardiac dysfunction, careful monitoring of cardiac function appears to be necessary in daily practice, particularly for patients with prior long-term trastuzumab treatments.
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The monoclonal antibody trastuzumab has improved the median disease free and overall survival of patients with early stage breast cancer that overexpresses the human epidermal growth factor receptor 2 (HER2). Despite this advance, some patients experience cancer relapse and novel approaches are always needed. One such advance is the monoclonal antibody pertuzumab, which prevents dimerisation between members of the HER family of transmembrane glycoprotein receptors.In this review, the authors analyse recent research which has focused on the development of new HER2 targeting agents for HER2-positive breast cancer, particularly pertuzumab, and its addition to trastuzumab and taxanes.Pertuzumab has significantly improved disease control in patients with advanced HER2 positive breast cancer when added to chemotherapy and trastuzumab. Although pertuzumab has also increased response rates in the preoperative setting, this has not yet translated into increased overall survival. The authors believe that future research should focus on improvements in novel biomarkers to select patients for new treatments.
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The anti-ErbB2 antibody trastuzumab has shown significant clinical benefits in metastatic breast cancer. However, resistance to trastuzumab is common. Heterodimerization between ErbB2 and other ErbBs may redundantly trigger cell proliferation signals and confer trastuzumab resistance. Here, we developed a bispecific anti-ErbB2 antibody using trastuzumab and pertuzumab, another ErbB2-specific humanized antibody that binds to a distinct epitope from trastuzumab. This bispecific antibody, denoted as TPL, retained the full binding activities of both parental antibodies and exhibited pharmacokinetic properties similar to those of a conventional immunoglobulin G molecule. Unexpectedly, TPL showed superior ErbB2 heterodimerization-blocking activity over the combination of both parental monoclonal antibodies, possibly through steric hindrance and/or inducing ErbB2 conformational change. Further data indicated that TPL potently abrogated ErbB2 signaling in trastuzumab-resistant breast cancer cell lines. In addition, we showed that TPL was far more effective than trastuzumab plus pertuzumab in inhibiting the growth of trastuzumab-resistant breast cancer cell lines, both in vitro and in vivo. Importantly, TPL treatment eradicated established trastuzumab-resistant tumors in tumor-bearing nude mice. Our results suggest that trastuzumab-resistant breast tumors remain dependent on ErbB2 signaling and that comprehensive blockade of ErbB2 heterodimerization may be an effective therapeutic avenue. The unique potential of TPL to overcome trastuzumab resistance warrants its consideration as a promising treatment in the clinic.
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