2017 Immuno-Oncology Medicines in Development
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Depatuxizumab Mafodotin (ABT-414)
Published OnlineFirst May 5, 2020; DOI: 10.1158/1535-7163.MCT-19-0609 MOLECULAR CANCER THERAPEUTICS | CANCER BIOLOGY AND TRANSLATIONAL STUDIES Depatuxizumab Mafodotin (ABT-414)-induced Glioblastoma Cell Death Requires EGFR Overexpression, but not EGFRY1068 Phosphorylation Caroline von Achenbach1, Manuela Silginer1, Vincent Blot2, William A. Weiss3, and Michael Weller1 ABSTRACT ◥ Glioblastomas commonly (40%) exhibit epidermal growth factor Exposure to ABT-414 in vivo eliminated EGFRvIII-expressing receptor EGFR amplification; half of these tumors carry the EGFR- tumor cells, and recurrent tumors were devoid of EGFRvIII vIII deletion variant characterized by an in-frame deletion of exons expression. There is no bystander killing of cells devoid of EGFR 2–7, resulting in constitutive EGFR activation. Although EGFR expression. Surprisingly, either exposure to EGF or to EGFR tyrosine kinase inhibitors had only modest effects in glioblastoma, tyrosin kinase inhibitors reduce EGFR protein levels and are thus novel therapeutic agents targeting amplified EGFR or EGFRvIII not strategies to promote ABT-414–induced cell killing. Further- continue to be developed. more, glioma cells overexpressing kinase-dead EGFR or EGFR- Depatuxizumab mafodotin (ABT-414) is an EGFR-targeting vIII retain binding of mAb 806 and sensitivity to ABT-414, antibody–drug conjugate consisting of the mAb 806 and a toxic allowing to dissociate EGFR phosphorylation from the emer- payload, monomethyl auristatin F. Because glioma cell lines and gence of the “active” EGFR conformation required for ABT-414 patient-derived glioma-initiating cell models expressed too little binding. EGFR in vitro to be ABT-414–sensitive, we generated glioma The combination of EGFR-targeting antibody–drug conju- sublines overexpressing EGFR or EGFRvIII to explore determinants gates with EGFR tyrosine kinase inhibitors carries a high risk of ABT-414–induced cell death. -
Precision Medicine for Human Cancers with Notch Signaling Dysregulation (Review)
INTERNATIONAL JOURNAL OF MOleCular meDICine 45: 279-297, 2020 Precision medicine for human cancers with Notch signaling dysregulation (Review) MASUKO KATOH1 and MASARU KATOH2 1M & M PrecMed, Tokyo 113-0033; 2Department of Omics Network, National Cancer Center, Tokyo 104-0045, Japan Received September 16, 2019; Accepted November 20, 2019 DOI: 10.3892/ijmm.2019.4418 Abstract. NOTCH1, NOTCH2, NOTCH3 and NOTCH4 are conjugate (ADC) Rova-T, and DLL3-targeting chimeric antigen transmembrane receptors that transduce juxtacrine signals of receptor‑modified T cells (CAR‑Ts), AMG 119, are promising the delta-like canonical Notch ligand (DLL)1, DLL3, DLL4, anti-cancer therapeutics, as are other ADCs or CAR-Ts targeting jagged canonical Notch ligand (JAG)1 and JAG2. Canonical tumor necrosis factor receptor superfamily member 17, Notch signaling activates the transcription of BMI1 proto-onco- CD19, CD22, CD30, CD79B, CD205, Claudin 18.2, fibro- gene polycomb ring finger, cyclin D1, CD44, cyclin dependent blast growth factor receptor (FGFR)2, FGFR3, receptor-type kinase inhibitor 1A, hes family bHLH transcription factor 1, tyrosine-protein kinase FLT3, HER2, hepatocyte growth factor hes related family bHLH transcription factor with YRPW receptor, NECTIN4, inactive tyrosine-protein kinase 7, inac- motif 1, MYC, NOTCH3, RE1 silencing transcription factor and tive tyrosine-protein kinase transmembrane receptor ROR1 transcription factor 7 in a cellular context-dependent manner, and tumor-associated calcium signal transducer 2. ADCs and while non-canonical Notch signaling activates NF-κB and Rac CAR-Ts could alter the therapeutic framework for refractory family small GTPase 1. Notch signaling is aberrantly activated cancers, especially diffuse-type gastric cancer, ovarian cancer in breast cancer, non-small-cell lung cancer and hematological and pancreatic cancer with peritoneal dissemination. -
Lung Cancer Drugs in the Pipeline
HemOnc today | JANUARY 10, 2016 | Healio.com/HemOnc 5 Lung Cancer Drugs in the Pipeline HEMONC TODAY presents this guide to drugs in phase 2 or phase 3 development for lung cancer-related indications. Clinicians can use this chart as a quick reference to learn about the status of those drugs that may be clinically significant to their practice. Generic name (Brand name, Manufacturer) Indication(s) Development status abemaciclib (Eli Lilly) non–small cell lung cancer phase 3 ABP 215 (Allergan/Amgen) non–small cell lung cancer (advanced disease) phase 3 ACP-196 (Acerta Pharma) non–small cell lung cancer (advanced disease) phase 2 ado-trastuzumab emtansine (Kadcyla, Genentech) non–small cell lung cancer (HER-2–positive disease) phase 2 afatinib (Gilotrif, Boehringer Ingelheim) lung cancer (squamous cell carcinoma) phase 3 aldoxorubicin (CytRx) small cell lung cancer phase 2 alectinib (Alecensa, Genentech) non–small cell lung cancer (second-line treatment of ALK-positive disease) phase 2 non–small cell lung cancer (first-line treatment of ALK-positive disease); phase 3 alisertib (Takeda) malignant mesothelioma, small cell lung cancer phase 2 avelumab (EMD Serono/Pfizer) non–small cell lung cancer phase 3 AZD9291 (AstraZeneca) non–small cell lung cancer (first-line treatment of advancedEGFR -positive disease; phase 3 second-line treatment of advanced EGFR-positive, T790M-positive disease) bavituximab (Peregrine Pharmaceuticals) non–small cell lung cancer (previously treated advanced/metastatic disease) phase 3 belinostat (Beleodaq, Spectrum -
Predictive QSAR Tools to Aid in Early Process Development of Monoclonal Antibodies
Predictive QSAR tools to aid in early process development of monoclonal antibodies John Micael Andreas Karlberg Published work submitted to Newcastle University for the degree of Doctor of Philosophy in the School of Engineering November 2019 Abstract Monoclonal antibodies (mAbs) have become one of the fastest growing markets for diagnostic and therapeutic treatments over the last 30 years with a global sales revenue around $89 billion reported in 2017. A popular framework widely used in pharmaceutical industries for designing manufacturing processes for mAbs is Quality by Design (QbD) due to providing a structured and systematic approach in investigation and screening process parameters that might influence the product quality. However, due to the large number of product quality attributes (CQAs) and process parameters that exist in an mAb process platform, extensive investigation is needed to characterise their impact on the product quality which makes the process development costly and time consuming. There is thus an urgent need for methods and tools that can be used for early risk-based selection of critical product properties and process factors to reduce the number of potential factors that have to be investigated, thereby aiding in speeding up the process development and reduce costs. In this study, a framework for predictive model development based on Quantitative Structure- Activity Relationship (QSAR) modelling was developed to link structural features and properties of mAbs to Hydrophobic Interaction Chromatography (HIC) retention times and expressed mAb yield from HEK cells. Model development was based on a structured approach for incremental model refinement and evaluation that aided in increasing model performance until becoming acceptable in accordance to the OECD guidelines for QSAR models. -
IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer
cancers Article IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer Mai Badarni 1,2, Manu Prasad 1,2 , Artemiy Golden 3, Baisali Bhattacharya 1,2, Liron Levin 4,5, Ksenia M. Yegodayev 1,2, Orr Dimitstein 2,6, Ben-Zion Joshua 2,7, Limor Cohen 1,2, Ekaterina Khrameeva 3, Dexin Kong 8 , Angel Porgador 1,2, Alex Braiman 1,2, Jennifer R. Grandis 9, Barak Rotblat 5,10,* and Moshe Elkabets 1,2,* 1 The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; [email protected] (M.B.); [email protected] (M.P.); [email protected] (B.B.); [email protected] (K.M.Y.); [email protected] (L.C.); [email protected] (A.P.); [email protected] (A.B.) 2 Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; [email protected] (O.D.); [email protected] (B.-Z.J.) 3 Center of Life Sciences, Skolkovo Institute of Science and Technology, 121205 Moscow, Russia; [email protected] (A.G.); [email protected] (E.K.) 4 Bioinformatics Core Facility, National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; [email protected] 5 The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel 6 Department of Otolaryngology—Head and Neck Surgery, Soroka University Medical Center, Beer-Sheva 84105, Israel 7 Citation: Badarni, M.; Prasad, M.; Department of Otorhinolaryngology and Head & Neck Surgery, Barzilay Medical Center, Ashkelon 7830604, Israel Golden, A.; Bhattacharya, B.; Levin, 8 School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin 300070, China; [email protected] L.; Yegodayev, K.M.; Dimitstein, O.; 9 Department of Otolaryngology—Head and Neck Surgery, University of California San Francisco, Joshua, B.-Z.; Cohen, L.; Khrameeva, San Francisco, CA 94143, USA; [email protected] E.; et al. -
Antibody Drug Conjugate Development in Gastrointestinal Cancers: Hopes and Hurdles from Clinical Trials
Wu et al. Cancer Drug Resist 2018;1:204-18 Cancer DOI: 10.20517/cdr.2018.16 Drug Resistance Review Open Access Antibody drug conjugate development in gastrointestinal cancers: hopes and hurdles from clinical trials Xiaorong Wu, Thomas Kilpatrick, Ian Chau Department of Medical oncology, Royal Marsden Hospital NHS foundation trust, Sutton SM2 5PT, UK. Correspondence to: Dr. Ian Chau, Department of Medical Oncology, Royal Marsden Hospital NHS foundation trust, Downs Road, Sutton SM2 5PT, UK. E-mail: [email protected] How to cite this article: Wu X, Kilpatrick T, Chau I. Antibody drug conjugate development in gastrointestinal cancers: hopes and hurdles from clinical trials. Cancer Drug Resist 2018;1:204-18. http://dx.doi.org/10.20517/cdr.2018.16 Received: 31 Aug 2018 First Decision: 8 Oct 2018 Revised: 13 Nov 2018 Accepted: 16 Nov 2018 Published: 19 Dec 2018 Science Editors: Elisa Giovannetti, Jose A. Rodriguez Copy Editor: Cui Yu Production Editor: Huan-Liang Wu Abstract Gastrointestinal (GI) cancers represent the leading cause of cancer-related mortality worldwide. Antibody drug conjugates (ADCs) are a rapidly growing new class of anti-cancer agents which may improve GI cancer patient survival. ADCs combine tumour-antigen specific antibodies with cytotoxic drugs to deliver tumour cell specific chemotherapy. Currently, only two ADCs [brentuximab vedotin and trastuzumab emtansine (T-DM1)] have been Food and Drug Administration approved for the treatment of lymphoma and metastatic breast cancer, respectively. Clinical research evaluating ADCs in GI cancers has shown limited success. In this review, we will retrace the relevant clinical trials investigating ADCs in GI cancers, especially ADCs targeting human epidermal growth receptor 2, mesothelin, guanylyl cyclase C, carcinogenic antigen-related cell adhesion molecule 5 (also known as CEACAM5) and other GI malignancy specific targets. -
Deciphering Molecular Mechanisms and Prioritizing Therapeutic Targets in Cardio-Oncology
Figure 1. This is a pilot view to explore the potential of EpiGraphDB to inform us about proteins that are linked to the pathophysiology of cancer and cardiovascular disease (CVD). For each cancer type (pink diamonds), we searched for cancer related proteins (light blue circles) that interact with other proteins identified as protein quantitative trait loci (pQTLs) for CVD (red diamonds for pathologies, orange triangles for risk factors). These pQTLs can be acting in cis (solid lines) or trans-acting (dotted lines). Proteins can interact either directly, a protein-protein interaction (dotted blue edges), or through the participation in the same pathway (red parallel lines). Shared pathways are represented with blue hexagons. We also queried which of these proteins are targeted by existing drugs. We found that the cancer drug cetuximab (yellow circle) inhibits EGFR. Other potential drugs are depicted in light brown hexagonal meta-nodes that are detailed below. Deciphering molecular mechanisms and prioritizing therapeutic targets in cardio-oncology Pau Erola1,2, Benjamin Elsworth1,2, Yi Liu2, Valeriia Haberland2 and Tom R Gaunt1,2,3 1 CRUK Integrative Cancer Epidemiology Programme; 2 MRC Integrative Epidemiology Unit, University of Bristol; 3 The Alan Turing Institute Cancer and cardiovascular disease (CVD) make by far the immense What is EpiGraphDB? contribution to the totality of human disease burden, and although mortality EpiGraphDB is an analytical platform and graph database that aims to is declining the number of those living with the disease shows little address the necessity of innovative and scalable approaches to harness evidence of change (Bhatnagar et al., Heart, 2016). -
Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix
United States International Trade Commission Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix USITC Publication 4208 December 2010 U.S. International Trade Commission COMMISSIONERS Deanna Tanner Okun, Chairman Irving A. Williamson, Vice Chairman Charlotte R. Lane Daniel R. Pearson Shara L. Aranoff Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix Publication 4208 December 2010 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 15, 2010, set forth at the end of this publication, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the United States International Trade Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement changes to the Pharmaceutical Appendix, effective on January 1, 2011. Table 1 International Nonproprietary Name (INN) products proposed for addition to the Pharmaceutical Appendix to the Harmonized Tariff Schedule INN CAS Number Abagovomab 792921-10-9 Aclidinium Bromide 320345-99-1 Aderbasib 791828-58-5 Adipiplon 840486-93-3 Adoprazine 222551-17-9 Afimoxifene 68392-35-8 Aflibercept 862111-32-8 Agatolimod -
The Pipeline Report 2016 Pipeline 2014 Autoimmune
THE PIPELINE REPORT 2016 PIPELINE 2014 AUTOIMMUNE PRODUCTS GENERATING BUZZ OTHER KEY PRODUCTS IN THE PIPELINE BIG-TIME Baricitinib Eli Lilly/Incyte Indication: RA (Ph.III) Romosozumab Amgen/UCB Sirukumab Janssen Biotech RA What the clinical trials found: The daily oral demonstrated superiority Osteoporosis (Ph.III) (Ph.III) compared to placebo after 12 weeks based on ACR20 response (Ph. Avatrombopag Astellas Pharma Anifrolumab Medarex/Med III RA-BEAM). The agent also proved superior to adalimumab on ITP/thrombocytopenia (Ph.III) Immune Systemic lupus erythema- tosus (Ph.III) key secondary objectives of ACR20 response and improvement in Elobixibat AstraZeneca CIC and DAS28-hsCRP score. A few occasional AEs were reported. IBS-C (Ph.III) Odanacatib Merck Osteoporosis (Ph.III) Credit Suisse Success Probability and inThought Comment: 70%. Lesinurad AstraZeneca Gout (Ph. III) Tildrakizumab Merck Psoriasis The JAK inhibitor appears to have similar efficacy and safety to (Ph.III) Pfizer’s Xeljanz. It was supposed to have a once daily vs. Xeljanz’s Alicaforsen Atlantic Healthcare Pouchitis/ulcerative colitis (Ph.III) Siponimod Novartis MS (Ph.III) twice daily advantage, but Xeljanz’s once daily formulation will likely be approved soon. It’ll be interesting to see if Lilly/Incyte Rituximab biosimilar Boehringer Infliximab biosimilar Pfizer RA Ingelheim RA (Ph.III) (Ph.III) can do something with patient access and price to improve upon Mongersen Celgene/Nogra RHB 104 RedHill Biopharma the poor performance of Xeljanz and expand the JAK inhibitor Pharma Crohn’s disease (Ph.III) Crohn’s disease (Ph.III) market. Expected launch: 2016 (Source: Credit Suisse) Etanercept biosimilar Coherus Sarilumad Regeneron RA (Ph.III) Credit Suisse forecast: $1.09 billion in global annual sales by 2020 Biosciences/Daiichi Sankyo/ Etrolizumab Roche Ulcerative A peek at 159 aspiring agents, with profiles on 17 that could shoot to stardom. -
Preclinical Efficacy of an Antibody–Drug Conjugate Targeting
Published OnlineFirst October 19, 2016; DOI: 10.1158/1535-7163.MCT-16-0449 Large Molecule Therapeutics Molecular Cancer Therapeutics Preclinical Efficacy of an Antibody–Drug Conjugate Targeting Mesothelin Correlates with Quantitative 89Zr-ImmunoPET Anton G.T. Terwisscha van Scheltinga1,2, Annie Ogasawara1, Glenn Pacheco1, Alexander N. Vanderbilt1, Jeff N. Tinianow1, Nidhi Gupta1, Dongwei Li1, Ron Firestein1, Jan Marik1, Suzie J. Scales1, and Simon-Peter Williams1 Abstract Antibody–drug conjugates (ADC) use monoclonal antibo- and HPAF-II, or mesothelioma MSTO-211H. Ex vivo analysis dies (mAb) as vehicles to deliver potent cytotoxic drugs selec- of mesothelin expression was performed using immunohis- tively to tumor cells expressing the target. Molecular imaging tochemistry. AMA-MMAE showed the greatest growth inhibi- with zirconium-89 (89Zr)-labeled mAbs recapitulates similar tion in OVCAR-3Â2.1, Capan-2, and HPAC tumors, which targeting biology and might help predict the efficacy of these showed target-specific tumor uptake of 89Zr-AMA. The less ADCs. An anti-mesothelin antibody (AMA, MMOT0530A) was responsive xenografts (AsPC-1, HPAF-II, and MSTO-211H) did used to make comparisons between its efficacy as an ADC and not show 89Zr-AMA uptake despite confirmed mesothelin its tumor uptake as measured by 89Zr immunoPET imaging. expression. ImmunoPET can demonstrate the necessary deliv- Mesothelin-targeted tumor growth inhibition by monomethyl ery, binding, and internalization of an ADC antibody in vivo auristatin E (MMAE), ADC AMA-MMAE (DMOT4039A), andthiscorrelateswiththeefficacy of mesothelin-targeted ADC was measured in mice bearing xenografts of ovarian cancer in tumors vulnerable to the cytotoxic drug delivered. Mol Cancer OVCAR-3Â2.1, pancreatic cancers Capan-2, HPAC, AsPC-1, Ther; 16(1); 134–42. -
Corneal Epithelial Findings in Patients with Multiple Myeloma Treated with Antibody–Drug Conjugate Belantamab Mafodotin in the Pivotal, Randomized, DREAMM-2 Study
Ophthalmol Ther https://doi.org/10.1007/s40123-020-00280-8 ORIGINAL RESEARCH Corneal Epithelial Findings in Patients with Multiple Myeloma Treated with Antibody–Drug Conjugate Belantamab Mafodotin in the Pivotal, Randomized, DREAMM-2 Study Asim V. Farooq . Simona Degli Esposti . Rakesh Popat . Praneetha Thulasi . Sagar Lonial . Ajay K. Nooka . Andrzej Jakubowiak . Douglas Sborov . Brian E. Zaugg . Ashraf Z. Badros . Bennie H. Jeng . Natalie S. Callander . Joanna Opalinska . January Baron . Trisha Piontek . Julie Byrne . Ira Gupta . Kathryn Colby Received: April 21, 2020 Ó The Author(s) 2020, corrected publication 2020 ABSTRACT monomethyl auristatin F (MMAF), to myeloma cells. In the phase II DREAMM-2 study Introduction: Patients with relapsed or refrac- (NCT03525678), single-agent belamaf (2.5 mg/kg) tory multiple myeloma (RRMM) represent an demonstrated clinically meaningful anti-mye- unmet clinical need. Belantamab mafodotin loma activity (overall response rate 32%) in (belamaf; GSK2857916) is a first-in-class anti- patients with heavily pretreated disease. Micro- body–drug conjugate (ADC; or immunoconju- cyst-like epithelial changes (MECs) were com- gate) that delivers a cytotoxic payload, mon, consistent with reports from other MMAF- containing ADCs. Methods: Corneal examination findings from Digital Features To view digital features for this article patients in DREAMM-2 were reviewed, and the go to https://doi.org/10.6084/m9.figshare.12326546. clinical descriptions and accompanying images The original version of this article was revised based upon recent changes to the FDA label and guidance on D. Sborov the use of belamaf. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA A. V. Farooq (&) Á A. -
Roche/Genentech Managed RG7986 ADC R/R NHL CHU Chugai Managed IONIS IONIS Managed 74 Status As of January 28, 2016 PRO Proximagen Managed
Roche 2015 results London, 28 January 2016 This presentation contains certain forward-looking statements. These forward-looking statements may be identified by words such as ‘believes’, ‘expects’, ‘anticipates’, ‘projects’, ‘intends’, ‘should’, ‘seeks’, ‘estimates’, ‘future’ or similar expressions or by discussion of, among other things, strategy, goals, plans or intentions. Various factors may cause actual results to differ materially in the future from those reflected in forward-looking statements contained in this presentation, among others: 1 pricing and product initiatives of competitors; 2 legislative and regulatory developments and economic conditions; 3 delay or inability in obtaining regulatory approvals or bringing products to market; 4 fluctuations in currency exchange rates and general financial market conditions; 5 uncertainties in the discovery, development or marketing of new products or new uses of existing products, including without limitation negative results of clinical trials or research projects, unexpected side-effects of pipeline or marketed products; 6 increased government pricing pressures; 7 interruptions in production; 8 loss of or inability to obtain adequate protection for intellectual property rights; 9 litigation; 10 loss of key executives or other employees; and 11 adverse publicity and news coverage. Any statements regarding earnings per share growth is not a profit forecast and should not be interpreted to mean that Roche’s earnings or earnings per share for this year or any subsequent period will necessarily match or exceed the historical published earnings or earnings per share of Roche. For marketed products discussed in this presentation, please see full prescribing information on our website www.roche.com All mentioned trademarks are legally protected.