Dimeric Her2-Specific Affibody Mediated Cisplatin-Loaded Nanoparticles for Tumor Enhanced Chemo-Radiotherapy

2021 ◽  
Author(s):  
Haijun Wang ◽  
Dianlong Jia ◽  
Dandan Yuan ◽  
Xiaolei Yin ◽  
Fengjiao Yuan ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Tumor Cells ◽  
Combined Therapy ◽  
Expression System ◽  
Growth Factor Receptor ◽  
High Energy ◽  
Tumor Growth Inhibition ◽  
Ros Generation ◽  
Her2 Positive

Abstract Background: Solid tumor hypoxic conditions fails to facilitate reactive oxygen species (ROS) generation and formation of DNA double-strand breaks (DSBs) induced by ionizing radiation, ultimately lead to a crucial role in radiotherapy resistance. Recently, there have been significant technical advances in nanomedicine aid to relieve hypoxia by in situ production of O2, serving as “radiosensitizer” to induce tumor cells more sensitive to ionizing radiation. However, the off-target damage of surrounding healthy tissues caused by such high-energy radiation is often unavoidable and the tumor cells at some distance from the focal spot of ionizing radiation may avoid damage. Therefore, there is an urgent need to exploit an intelligently targeted nanoplatform to integrate both precisely enhance RT-induced DNA damage and combined therapy.Results: Herein, we developed human epidermal growth factor receptor 2 (Her2)-specific dimeric affibody (ZHer2) mediated cisplatin-loaded mesoporous polydopamine/MnO2/polydopamine nanoparticles (Pt@mPDA/MnO2/PDA-ZHer2 NPs) for MRI and enhanced chemo-radiotherapy of Her2-positive ovarian tumor. These NPs are biodegradable under simulated tumor microenvironment, resulting in cisplatin accelerated release, as well as production of O2. ZHer2 produced by the E. coli expression system endowed NPs with Her2-dependent binding ability in the Her2-positive SKOV-3 cells. In vivo MRI studies revealed an obvious T1 contrast enhancement at the tumor site. Moreover, these NPs achieved efficient tumor homing and penetration, attributing to the efficient internalization and penetrability of ZHer2. Under X-Ray irradiation, these NPs exhibited the highest tumor growth inhibition effect. Immunofluorescence assay showed these NPs significantly reduced the expression of HIF-1α and improved ROS level, resulting in radiosensitization. Conclusions: The nanocarriers constructed in this study integrated Her2 targeting, diagnosis, RT sensitization, thus providing a new idea for clinical translation in tumor theranostics.

scholarly journals Dimeric Her2-specific affibody mediated cisplatin-loaded nanoparticles for tumor enhanced chemo-radiotherapy

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Haijun Wang ◽  
Dianlong Jia ◽  
Dandan Yuan ◽  
Xiaolei Yin ◽  
Fengjiao Yuan ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Tumor Cells ◽  
Focal Point ◽  
Combined Therapy ◽  
Expression System ◽  
Growth Factor Receptor ◽  
High Energy ◽  
Immunofluorescence Assay ◽  
Her2 Positive

Abstract Background Solid tumor hypoxic conditions prevent the generation of reactive oxygen species (ROS) and the formation of DNA double-strand breaks (DSBs) induced by ionizing radiation, which ultimately contributes to radiotherapy (RT) resistance. Recently, there have been significant technical advances in nanomedicine to reduce hypoxia by facilitating in situ O2 production, which in turn serves as a “radiosensitizer” to increase the sensitivity of tumor cells to ionizing radiation. However, off-target damage to the tumor-surrounding healthy tissue by high-energy radiation is often unavoidable, and tumor cells that are further away from the focal point of ionizing radiation may avoid damage. Therefore, there is an urgent need to develop an intelligent targeted nanoplatform to enable precise enhanced RT-induced DNA damage and combined therapy. Results Human epidermal growth factor receptor 2 (Her2)-specific dimeric affibody (ZHer2) mediated cisplatin-loaded mesoporous polydopamine/MnO2/polydopamine nanoparticles (Pt@mPDA/MnO2/PDA-ZHer2 NPs) for MRI and enhanced chemo-radiotherapy of Her2-positive ovarian tumors is reported. These NPs are biodegradable under a simulated tumor microenvironment, resulting in accelerated cisplatin release, as well as localized production of O2. ZHer2, produced using the E. coli expression system, endowed NPs with Her2-dependent binding ability in Her2-positive SKOV-3 cells. An in vivo MRI revealed obvious T1 contrast enhancement at the tumor site. Moreover, these NPs achieved efficient tumor homing and penetration via the efficient internalization and penetrability of ZHer2. These NPs exhibited excellent inhibition of tumor growth with X-ray irradiation. An immunofluorescence assay showed that these NPs significantly reduced the expression of HIF-1α and improved ROS levels, resulting in radiosensitization. Conclusions The nanocarriers described in the present study integrated Her2 targeting, diagnosis and RT sensitization into a single platform, thus providing a novel approach for translational tumor theranostics. Graphic abstract

scholarly journals Structural and Electrophysiological Changes in a Model of Cardiotoxicity Induced by Anthracycline Combined With Trastuzumab

2021 ◽  
Vol 12 ◽  
Author(s):  
Claudia Altomare ◽  
Alessandra Maria Lodrini ◽  
Giuseppina Milano ◽  
Vanessa Biemmi ◽  
Edoardo Lazzarini ◽  
...  
Keyword(s):  
Combined Therapy ◽  
Combined Treatment ◽  
Growth Factor Receptor ◽  
Left Ventricular ◽  
Her2 Positive ◽  
Adult Rats ◽  
Adaptive Changes ◽  
Two Agents ◽  
Intracellular Ca

BackgroundCombined treatment with anthracyclines (e.g., doxorubicin; Dox) and trastuzumab (Trz), a humanized anti-human epidermal growth factor receptor 2 (HER2; ErbB2) antibody, in patients with HER2-positive cancer is limited by cardiotoxicity, as manifested by contractile dysfunction and arrhythmia. The respective roles of the two agents in the cardiotoxicity of the combined therapy are incompletely understood.ObjectiveTo assess cardiac performance, T-tubule organization, electrophysiological changes and intracellular Ca2+ handling in cardiac myocytes (CMs) using an in vivo rat model of Dox/Trz-related cardiotoxicity.Methods and ResultsAdult rats received 6 doses of either Dox or Trz, or the two agents sequentially. Dox-mediated left ventricular (LV) dysfunction was aggravated by Trz administration. Dox treatment, but not Trz, induced T-tubule disarray. Moreover, Dox, but not Trz monotherapy, induced prolonged action potential duration (APD), increased incidence of delayed afterdepolarizations (DADs) and beat-to-beat variability of repolarization (BVR), and slower Ca2+ transient decay. Although APD, DADs, BVR and Ca2+ transient decay recovered over time after the cessation of Dox treatment, subsequent Trz administration exacerbated these abnormalities. Trz, but not Dox, reduced Ca2+ transient amplitude and SR Ca2+ content, although only Dox treatment was associated with SERCA downregulation. Finally, Dox treatment increased Ca2+ spark frequency, resting Ca2+ waves, sarcoplasmic reticulum (SR) Ca2+ leak, and long-lasting Ca2+ release events (so-called Ca2+ “embers”), partially reproduced by Trz treatment.ConclusionThese results suggest that in vivo Dox but not Trz administration causes T-tubule disarray and pronounced changes in electrical activity of CMs. While adaptive changes may account for normal AP shape and reduced DADs late after Dox administration, subsequent Trz administration interferes with such adaptive changes. Intracellular Ca2+ handling was differently affected by Dox and Trz treatment, leading to SR instability in both cases. These findings illustrate the specific roles of Dox and Trz, and their interactions in cardiotoxicity and arrhythmogenicity.

scholarly journals Imaging-Guided Therapy Simultaneously Targeting HER2 and EpCAM with Trastuzumab and EpCAM-Directed Toxin Provides Additive Effect in Ovarian Cancer Model

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3939
Author(s):  
Tianqi Xu ◽  
Anzhelika Vorobyeva ◽  
Alexey Schulga ◽  
Elena Konovalova ◽  
Olga Vorontsova ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Growth Factor Receptor ◽  
Repeated Administration ◽  
Ovarian Cancer Cells ◽  
Her2 Positive ◽  
Efficient Treatment ◽  
Pseudomonas Exotoxin A ◽  
Epidermal Growth

Efficient treatment of disseminated ovarian cancer (OC) is challenging due to its heterogeneity and chemoresistance. Overexpression of human epidermal growth factor receptor 2 (HER2) and epithelial cell adhesion molecule (EpCAM) in approx. 30% and 70% of ovarian cancers, respectively, allows for co-targeted treatment. The clinical efficacy of the monoclonal antibody trastuzumab in patients with HER2-positive breast, gastric and gastroesophageal cancers makes it readily available as the HER2-targeting component. As the EpCAM-targeting component, we investigated the designed ankyrin repeat protein (DARPin) Ec1 fused to a truncated variant of Pseudomonas exotoxin A with reduced immunogenicity and low general toxicity (LoPE). Ec1-LoPE was radiolabeled, evaluated in ovarian cancer cells in vitro and its biodistribution and tumor-targeting properties were studied in vivo. The therapeutic efficacy of Ec1-LoPE alone and in combination with trastuzumab was studied in mice bearing EpCAM- and HER2-expressing SKOV3 xenografts. SPECT/CT imaging enabled visualization of EpCAM and HER2 expression in the tumors. Co-treatment using Ec1-LoPE and trastuzumab was more effective at reducing tumor growth and prolonged the median survival of mice compared with mice in the control and monotherapy groups. Repeated administration of Ec1-LoPE was well tolerated without signs of hepatic or kidney toxicity. Co-treatment with trastuzumab and Ec1-LoPE might be a potential therapeutic strategy for HER2- and EpCAM-positive OC.

scholarly journals Highly Differentiated Anti-CD47 Antibody, AO-176, Potently Inhibits Hematologic Malignancies Alone and in Combination

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1844-1844
Author(s):  
John Richards ◽  
Myriam N Bouchlaka ◽  
Robyn J Puro ◽  
Ben J Capoccia ◽  
Ronald R Hiebsch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combination Therapy ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Cells ◽  
Tumor Growth Inhibition ◽  
Employment Equity ◽  
Equity Ownership

AO-176 is a highly differentiated, humanized anti-CD47 IgG2 antibody that is unique among agents in this class of checkpoint inhibitors. AO-176 works by blocking the "don't eat me" signal, the standard mechanism of anti-CD47 antibodies, but also by directly killing tumor cells. Importantly, AO-176 binds preferentially to tumor cells, compared to normal cells, and binds even more potently to tumors in their acidic microenvironment (low pH). Hematological neoplasms are the fourth most frequently diagnosed cancers in both men and women and account for approximately 10% of all cancers. Here we describe AO-176, a highly differentiated anti-CD47 antibody that potently targets hematologic cancers in vitro and in vivo. As a single agent, AO-176 not only promotes phagocytosis (15-45%, EC50 = 0.33-4.1 µg/ml) of hematologic tumor cell lines (acute myeloid leukemia, non-Hodgkin's lymphoma, multiple myeloma, and T cell leukemia) but also directly targets and kills tumor cells (18-46% Annexin V positivity, EC50 = 0.63-10 µg/ml) in a non-ADCC manner. In combination with agents targeting CD20 (rituximab) or CD38 (daratumumab), AO-176 mediates enhanced phagocytosis of lymphoma and multiple myeloma cell lines, respectively. In vivo, AO-176 mediates potent monotherapy tumor growth inhibition of hematologic tumors including Raji B cell lymphoma and RPMI-8226 multiple myeloma xenograft models in a dose-dependent manner. Concomitant with tumor growth inhibition, immune cell infiltrates were observed with elevated numbers of macrophage and dendritic cells, along with increased pro-inflammatory cytokine levels in AO-176 treated animals. When combined with bortezomib, AO-176 was able to elicit complete tumor regression (100% CR in 10/10 animals treated with either 10 or 25 mg/kg AO-176 + 1 mg/kg bortezomib) with no detectable tumor out to 100 days at study termination. Overall survival was also greatly improved following combination therapy compared to animals treated with bortezomib or AO-176 alone. These data show that AO-176 exhibits promising monotherapy and combination therapy activity, both in vitro and in vivo, against hematologic cancers. These findings also add to the previously reported anti-tumor efficacy exhibited by AO-176 in solid tumor xenografts representing ovarian, gastric and breast cancer. With AO-176's highly differentiated MOA and binding characteristics, it may have the potential to improve upon the safety and efficacy profiles relative to other agents in this class. AO-176 is currently being evaluated in a Phase 1 clinical trial (NCT03834948) for the treatment of patients with select solid tumors. Disclosures Richards: Arch Oncology Inc.: Employment, Equity Ownership, Other: Salary. Bouchlaka:Arch Oncology Inc.: Consultancy, Equity Ownership. Puro:Arch Oncology Inc.: Employment, Equity Ownership. Capoccia:Arch Oncology Inc.: Employment, Equity Ownership. Hiebsch:Arch Oncology Inc.: Employment, Equity Ownership. Donio:Arch Oncology Inc.: Employment, Equity Ownership. Wilson:Arch Oncology Inc.: Employment, Equity Ownership. Chakraborty:Arch Oncology Inc.: Employment, Equity Ownership. Sung:Arch Oncology Inc.: Employment, Equity Ownership. Pereira:Arch Oncology Inc.: Employment, Equity Ownership.

scholarly journals Exosomes containing miRNAs targeting HER2 synthesis and engineered to adhere to HER2 on tumor cells surface exhibit enhanced antitumor activity

2020 ◽  
Author(s):  
Lei Wang ◽  
Xusha Zhou ◽  
Weixuan Zou ◽  
Yinglin Wu ◽  
Jing Zhao ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Growth Factor Receptor ◽  
Wide Range ◽  
Epidermal Growth

Abstract Background: Exosomes are small, cellular membrane-derived vesicles with a diameter of 50-150 nm. Exosomes are considered ideal drug delivery systems with a wide range of applications in various diseases, including cancer. However, nonspecific delivery of therapeutic agents by exosomes in vivo remains challenging. H uman epidermal growth factor receptor 2 (HER2) is an epidermal growth factor receptor tyrosine kinase, and its overexpression is usually associated with cell survival and tumor progression in various cancers. In this study, we aim to develop novel exosomes with dual HER2-targeting ability as a nanoparticle delivery vehicle to enhance antitumor efficacy in vivo . Results: Here, we report the generation of two kinds of exosomes carrying miRNAs designed to block HER2 synthesis and consequently kill tumor cells. 293-miR-HER2 exosomes package and deliver designed miRNAs to cells to block HER2 synthesis. These exosomes kill cancer cells dependent on HER2 for survival but do not affect cells that lack HER2 or that are engineered to express HER2 but are not dependent on it for survival. In contrast, 293-miR-XS-HER2 exosomes carry an additional peptide, which enables them to adhere to HER2 on the surface of cancer cells. Consequently, these exosomes preferentially enter and kill cells with surface expression of HER2. 293-miR-XS-HER2 exosomes are significantly more effective than the 293-miR-HER2 exosomes in shrinking HER2-positive tumors implanted in mice. Conclusions: Collectively, as novel antitumor drug delivery vehicles, HER2 dual-targeting exosomes exhibit increased target-specific delivery efficiency and can be further utilized to develop new nanoparticle-based targeted therapies.

The effect of monotherapy and combined therapy with NSC-631570 (Ukrain) on growth of low- and high-metastasizing B16 melanoma in mice

2010 ◽  
Vol 17 (4) ◽  
pp. 339-349 ◽  
Author(s):  
LM Skivka ◽  
YaM Susak ◽  
OO Trompak ◽  
YuI Kudryavets ◽  
N Bezdeneznikh ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Combined Therapy ◽  
Tumor Growth Inhibition ◽  
Cell Cycle Distribution ◽  
Colorimetric Determination ◽  
Chelidonium Majus ◽  
Melanoma B16

Background. NSC-631570 (Ukrain) is a semisynthetic derivative of the Chelidonium majus alcaloids and the alkylans thiotepa. It exerts a selective cytotoxic effect on tumor cells in vitro and in vivo and shows the ability to modulate immunocyte functions. Purpose. The aim of our work was to carry out a comparative investigation of the effects of NSC-631570 alone or in combination with pathogen-associated molecules (PAM) on the growth of low- and high-metastasizing melanoma B16 in mice. Methods. NSC-631570 was administered intravenously and PAM intramuscularly to tumor-bearing mice seven times every third day, starting from the second day after the transplantation of tumor cells. The effect of monotherapy and combined therapy on tumor growth was evaluated by the indices of tumor growth inhibition in experimental animals. Cell cycle distribution of cancer cells was determined by flow cytometry. TAP1 and TAP2 expression was evaluated by RT-PCR. The metabolic activity of phagocytes was determined by NBT-test, phagocytosis was tested by flow cytometry, and arginase activity was estimated by colorimetric determination of urea. Results. Combined therapy and monotherapy with NSC-631570 resulted in significant inhibition of tumor growth in melanoma-bearing mice. Monotherapy with Ukrain was more effective in mice with high-metastasizing tumors. The therapeutic efficacy of NSC-631570 used in combination with PAM was more expressed in mice with low-metastasizing melanoma. Conclusion. The effectiveness of monotherapy and combined therapy with NSC-631570 in the treatment of melanoma B16 depends on the biological properties of the tumor and the immune state of the organism.

scholarly journals Ultrasound Targeted Microbubble Destruction Combined With Fe-MOF Based Bio-/Enzyme-Mimics Nanoparticles for Treating of Cancer

2020 ◽  
Author(s):  
Xi Xiang ◽  
Houqing Pang ◽  
Tian Ma ◽  
Fangxue Du ◽  
Ling Li ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Treatment Resistance ◽  
Ros Generation ◽  
Dead Cell ◽  
Cytotoxicity Test ◽  
Enzyme Mimics ◽  
Tumor Cell Membrane ◽  
Efficient Treatment

Abstract Background: Cancer urgently needs a new strategy for its recurrence and treatment resistance with the existing treatments. Fe-based metal-organic frameworks (MOFs) had the potential in ROS generation due to Fenton catalysis, which has been shown to be effective in antitumor therapy. However, Fenton catalysis requires sufficient H2O2 as the reactant to generate hydroxyl radical. Therefore, further improvement of Fe-MOF is needed. In the research, bio-/enzyme-mimics nanoparticles FeN200@GOx@M were synthesized and were used combined with ultrasound targeted microbubble destruction (UTMD) as a novel method for cancer therapy. Methods: FeN200@GOx@M was synthesized by loading GOx and encapsulating tumor cell membrane. The nanostructures were characterized by SEM, TEM, XRD, EDS, XPS, and so on. The anti-tumor efficiency of FeN200@GOx@M was evaluated by cytotoxicity test, live/dead cell staining and apoptosis ratio in vitro. The combination of FeN200@GOx@M and UTMD was applied in vivo to verify the enhancement of anti-tumor effect of UTMD on FeN200@[email protected]: FeN200@GOx@M was successfully synthesized. FeN200@GOx@M was most easily intake by A2780 tumor cells, generated the most ROS in tumor cells, and induced the most apoptotic tumor cells in vitro. In addition, UTMD technology further improved the anti-tumor efficiency in vivo due to its sonoporation, which helped create reversible holes in cell membranes for easier been destroyed by FeN200@GOx@M. Conclusion: Fe-MOF based bio-/enzyme-mimics nanoparticles FeN200@GOx@M had excellent anti-tumor efficiency. And UTMD can improve the therapeutic effectiveness. The combination of FeN200@GOx@M and UTMD provided a novel, safe, and efficient treatment strategy for cancer.

scholarly journals Antibody-Based Targeting of Interferon-Beta-1a Mutein in HER2-Positive Cancer Enhances Antitumor Effects Through Immune Responses and Direct Cell Killing

2021 ◽  
Vol 11 ◽  
Author(s):  
Chan Gyu Lee ◽  
TaeEun Kim ◽  
Sungyoul Hong ◽  
Jongwan Chu ◽  
Ju Eun Kang ◽  
...  
Keyword(s):  
Tumor Targeting ◽  
Antitumor Effect ◽  
Immune Cell ◽  
Tumor Growth Inhibition ◽  
Type I ◽  
Biophysical Properties ◽  
Her2 Positive ◽  
Antitumor Effects ◽  
Direct Cell

Type I interferon (IFN) has been approved as an anticancer agent to treat some malignancies. However, IFNs have a short in vivo half-life, systemic toxicity, and poor biophysical properties, which prevent it from being widely used for cancer therapy. This study aimed to construct recombinant IFN-β-1a mutein immunocytokines that comprise a human epidermal growth factor receptor 2 (HER2)-targeting antibody and IFN-β muteins with an additional glycosylation, which can overcome the limitation of the cytokine itself. Hence, the molecular design aims to 1) enhance productivity and biophysical properties by adding secondary glycosylation in IFN-β, 2) increase the therapeutic index of IFN-β therapy by preferential retention at the tumor by possessing high affinity for HER2-expressing cancer cells, and 3) improve the pharmacokinetics and, thus, the convenience of IFN-β administration. The yield of trastuzumab-IFN-β mutein was higher than that of trastuzumab-wild-type IFN-β in the mammalian cell culture system. Trastuzumab-IFN-β mutein showed similar IFN activity and HER2-targeting ability equivalent to that of IFN-β mutein and trastuzumab, respectively. Trastuzumab-IFN-β mutein directly inhibited the growth of HER2-positive gastric cancer cell lines and was more effective than trastuzumab or IFN-β mutein alone. Trastuzumab-IFN-β mutein and IFN-β mutein displayed enhanced immune cell-mediated cytotoxicity. Collectively, trastuzumab-IFN-β mutein may have indirect immune cell-mediated antitumor effects and direct cell growth inhibitory effects. Tumor-targeting effect of trastuzumab-IFN-β mutein was analyzed using in vivo fluorescence imaging. The accumulation of trastuzumab-IFN-β mutein was observed in HER2-positive tumors rather than other tissues except the liver. To evaluate the both direct tumor growth inhibition effect and indirect immune cell-mediated antitumor effect, we tested the effect of trastuzumab-IFN-β mutein in HER2-positive cancer xenograft models using nude mice or humanized mice. Trastuzumab-IFN-β mutein could significantly enhance tumor regression when compared with trastuzumab or IFN-β mutein. In addition, an increase in tumor-infiltrating lymphocytes was observed in the trastuzumab-IFN-β mutein-treated group, implying that the tumor-targeting IFN-β may have an enhanced antitumor effect through increased immune response. Therefore, targeting IFN-β with an anti-HER2 monoclonal antibody makes the immunocytokine more potent than either agent alone. These novel findings suggest that trastuzumab-IFN-β mutein merits clinical evaluation as a new candidate of anticancer therapeutics.

scholarly journals Synthesis of site-specific antibody-drug conjugates by ADP-ribosyl cyclases

2020 ◽  
Vol 6 (23) ◽  
pp. eaba6752 ◽  
Author(s):  
Zhefu Dai ◽  
Xiao-Nan Zhang ◽  
Fariborz Nasertorabi ◽  
Qinqin Cheng ◽  
Jiawei Li ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Reaction Times ◽  
Single Step ◽  
Her2 Positive ◽  
Site Specific ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Most of the current antibody-drug conjugates (ADCs) in clinic are heterogeneous mixtures. To produce homogeneous ADCs, established procedures often require multiple steps or long reaction times. The introduced mutations or foreign sequences may cause high immunogenicity. Here, we explore a new concept of transforming CD38 enzymatic activity into a facile approach for generating site-specific ADCs. This was achieved through coupling bifunctional antibody-CD38 fusion proteins with designer dinucleotide-based covalent inhibitors with stably attached payloads. The resulting adenosine diphosphate–ribosyl cyclase–enabled ADC (ARC-ADC) with a drug-to-antibody ratio of 2 could be rapidly generated through single-step conjugation. The generated ARC-ADC targeting human epidermal growth factor receptor 2 (HER2) displays excellent stability and potency against HER2-positive breast cancer both in vitro and in vivo. This proof-of-concept study demonstrates a new strategy for production of site-specific ADCs. It may provide a general approach for the development of a novel class of ADCs with potentially enhanced properties.

Arginine methylation of EGFR in circulating tumor cells: A new biomarker for predicting resistance to anti-EGFR agents.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3590-3590
Author(s):  
Krittiya Korphaisarn ◽  
Chao-Kai Chou ◽  
Weiya Xia ◽  
Callisia Clarke ◽  
Jennifer S Davis ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Arginine Methylation ◽  
Rank Test ◽  
Positive Staining ◽  
Egfr Ligands ◽  
Kaplan Meier

3590 Background: Arginine methylation of the epidermal growth factor receptor (meEGFR) increases binding affinity of EGF and other EGFR ligands, reduces the efficacy of anti-EGFR agents in vivo, and is reported to have a role in predicting response to anti-EGFR agents. This study aimed to investigate the predictive impact of meEGFR in metastatic colorectal cancer (mCRC) patients (pts) treated with anti-EGFR agents using blood-based testing. Methods: 15 mL of blood were collected from mCRC pts with documented disease progression following anti-EGFR treatment (Rx). Circulating tumor cells (CTCs) were isolated using antibody (ab)-independent micro-fluidic cassette-based technology (Parsortix system), which separates CTCs on the basis of size and deformability. CTCs were identified based on negative staining for CD45ab and positive staining for EpCAMab. meEGFR was identified based on positive staining for me-R198/200ab on CTCs. Associations between meEGFR-CTCs and total CTCs with progression free survival (PFS) were determined by Kaplan-Meier method and compared by the log-rank test. Results: A total of 47 mCRC pts were prospectively included in this study. CTCs were identified in 30 out of 47 cases (64%). Of those 30, meEGFR-CTCs were identified in 19 cases (63%). Mean total CTCs and meEGFR-CTCs counts were 3.6 (range 0-52) and 2.3 (range 0-30) cells per 7.5ml, respectively. There was no association between meEGFR-CTCs and clinic-pathological features (age, sex, tumor site & grade), line of anti-EGFR Rx, previous irinotecan used, or NRAS, BRAF, PIK3CA, and MSI status. However, in RASwt/BRAFwtmCRC pts, high levels of meEGFR ratio (defined as > 0.25 meEGFR-CTCs per total CTCs) was associated with significantly inferior PFS with anti-EGFR Rx (median PFS 5.4 mo vs. 8 mo, HR 3.4, 95% CI of 1.5-7.9, P = 0.004). By contrast, high levels of total CTCs ( > 3 cells/per 7.5 ml) had no impact on PFS with anti-EGFR Rx. Conclusions: We have successfully isolated CTCs from mCRC pts’ blood using Parsortix system. Elevated levels of arginine methylated EGFR is associated with a shorter PFS with anti-EGFR-based Rx. Assessment of meEGFR-CTCs may provide a “liquid biopsy” biomarker for reduced efficacy from anti-EGFR Rx.

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