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Affibody molecules are artificial proteins that can recognize cancer-related molecular abnormalities in the living body. Clinical studies demonstrated that Affibody molecules can be successfully used for radionuclide diagnostics. Targeted radionuclide therapy selectively delivers cytotoxic radionuclides to malignant tumors, thus sparing normal tissues. For radionuclide therapy, Affibody molecules were re-engineered to decrease accumulation in the kidneys. This study has demonstrated that radionuclide therapy using re-engineered Affibody molecules increases the survival of immunodeficient mice bearing human tumors. The therapy was more efficient than the treatment with a monoclonal antibody, which is currently used in clinical practice. The best results were obtained when both the antibody and radiolabeled Affibody molecules were used simultaneously. This work provides a preclinical rationale for a potentially more efficient treatment in HER2-positive cancers. ABY-027 is a scaffold-protein-based cancer-targeting agent. ABY-027 includes the second-generation Affibody molecule Z[sub.HER2:2891], which binds to human epidermal growth factor receptor type 2 (HER2). An engineered albumin-binding domain is fused to Z[sub.HER2:2891] to reduce renal uptake and increase bioavailability. The agent can be site-specifically labeled with a beta-emitting radionuclide [sup.177]Lu using a DOTA chelator. The goals of this study were to test the hypotheses that a targeted radionuclide therapy using [[sup.177]Lu]Lu-ABY-027 could extend the survival of mice with HER2-expressing human xenografts and that co-treatment with [[sup.177]Lu]Lu-ABY-027 and the HER2-targeting antibody trastuzumab could enhance this effect. Balb/C nu/nu mice bearing HER2-expressing SKOV-3 xenografts were used as in vivo models. A pre-injection of trastuzumab did not reduce the uptake of [[sup.177]Lu]Lu-ABY-027 in tumors. Mice were treated with [[sup.177]Lu]Lu-ABY-027 or trastuzumab as monotherapies and a combination of these therapies. Mice treated with vehicle or unlabeled ABY-027 were used as controls. Targeted monotherapy using [[sup.177]Lu]Lu-ABY-027 improved the survival of mice and was more efficient than trastuzumab monotherapy. A combination of therapies utilizing [[sup.177]Lu]Lu-ABY-027 and trastuzumab improved the treatment outcome in comparison with monotherapies using these agents. In conclusion, [[sup.177]Lu]Lu-ABY-027 alone or in combination with trastuzumab could be a new potential agent for the treatment of HER2-expressing tumors.

Purpose: The unique structure of nanobodies is advantageous for the development of radiopharmaceuticals for nuclear medicine. Nanobodies targeted to human epidermal growth factor receptor 2 (HER2) can be used as tools for the imaging and therapy of HER2-overexpressing tumors. In this study, we aimed to describe the generation of a [sup.131]I-labeled anti-HER2 nanobody as a targeted radionuclide therapy (TRNT) agent for HER2-positive breast cancer. Methods: The anti-HER2 nanobody NM-02 was labeled with [sup.131]I using the iodogen method, and its radiochemical purity and stability in vitro were assessed. The pharmacokinetic profile of [sup.131]I-NM-02 was investigated in normal mice. Tumor accumulation, biodistribution, and therapeutic potential of [sup.131]I-NM-02 were evaluated in HER2-positive SKBR3 xenografts; HER2- negative MB-MDA-231 xenografts were used as the control group. Results: [sup.131]I-NM-02 could be readily prepared with satisfactory radiochemical purity and stability in vitro. Apparent tumor uptake was observed in HER2-positive tumor-bearing mice with rapid blood clearance and favorable biodistribution. [sup.131]I- NM-02 could significantly inhibit tumor growth and extend the life of these mice with good organ compatibility. Negligible tumor accumulation and inhibitory effects of [sup.131]I-NM-02 were observed in the negative control group. Conclusion: [sup.131]I-NM-02 has the potential to be explored as a novel tool for TRNT of HER2-positive breast cancer. Keywords: human epidermal growth factor receptor 2, nanobody, [sup.131]I, targeted radionuclide therapy

Background HER2-targeting agents have dramatically changed the therapeutic landscape of HER2+ advanced breast cancer (ABC). Within a short time frame, the rapid introduction of new therapeutics has led to the approval of pertuzumab combined with trastuzumab and a taxane in first-line, and trastuzumab emtansine (T-DM1) in second-line. Thereby, evidence of T-DM1 efficacy following trastuzumab/pertuzumab combination is limited, with data from some retrospective reports suggesting lower activity. The purpose of the present study is to investigate T-DM1 efficacy in pertuzumab-pretreated and pertuzumab naïve HER2 positive ABC patients. We also aimed to provide evidence on the exposure to different drugs sequences including pertuzumab and T-DM1 in HER2 positive cell lines. Methods The biology of HER2 was investigated in vitro through sequential exposure of resistant HER2 + breast cancer cell lines to trastuzumab, pertuzumab, and their combination. In vitro experiments were paralleled by the analysis of data from 555 HER2 + ABC patients treated with T-DM1 and evaluation of T-DM1 efficacy in the 371 patients who received it in second line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models. Results We herein show evidence of lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Lower T-DM1 efficacy was associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. HER2 downregulation at the membrane level was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients. Among the 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis of advanced disease and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients ( p  = 0.0006 and 0.03 for OS and PFS2, respectively). Conclusions Our data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 in cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.

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.