Study Protocol-Related Adverse Event Should Be Recorded from the Time of Informed Consent
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Prior Approaches and Future Directions Marna Williams1, Anna Spreafico2, Kapil Vashisht3, Mary Jane Hinrichs4
Author Manuscript Published OnlineFirst on June 16, 2020; DOI: 10.1158/1535-7163.MCT-19-0993 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Patient Selection Strategies to Maximize Therapeutic Index of Antibody Drug Conjugates: Prior Approaches and Future Directions Marna Williams1, Anna Spreafico2, Kapil Vashisht3, Mary Jane Hinrichs4 1Translational Medicine, Oncology, AstraZeneca, Gaithersburg, USA 2Drug Development Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada 3AstraZeneca, Gaithersburg, USA. 4Early Development Oncology, Ipsen LLC, USA Corresponding author: Marna Williams Email: [email protected] Postal address: One MedImmune Way, Gaithersburg, MD, 20878 Phone: 301-398-1241 Fax: 240-306-1545 Running title Patient Selection Strategies for Antibody Drug Conjugates Keywords Antibody drug conjugates; therapeutic index; patient selection; biomarkers; cancer Conflicts of interest This study was funded by AstraZeneca. MW, KV and MJH are all current or former employees of AstraZeneca with stock/stock options in AstraZeneca. AS has been Advisory Board Consultant to Merck, Bristol-Myers Squibb, Novartis, Oncorus, Janssen, and has received Grant/Research support from Novartis, Bristol-Myers Squibb, Symphogen AstraZeneca/Medimmune, Merck, Bayer, Surface Oncology, Northern Biologics, Janssen Oncology/Johnson & Johnson, Roche, Regeneron, and Alkermes. Word count: Abstract: 197 Manuscript: 5,268 (excluding abstract) + 683 figure/table legends and footnotes Figures/tables: 5 (as agreed) 1 Downloaded from mct.aacrjournals.org on September 24, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 16, 2020; DOI: 10.1158/1535-7163.MCT-19-0993 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. -
For Acute Myeloid Leukemia
Published OnlineFirst September 21, 2010; DOI: 10.1158/1078-0432.CCR-10-0382 Published OnlineFirst on September 21, 2010 as 10.1158/1078-0432.CCR-10-0382 Clinical Therapy Clinical Cancer Research Sequential Cytarabine and α-Particle Immunotherapy with Bismuth-213–Lintuzumab (HuM195) for Acute Myeloid Leukemia Todd L. Rosenblat1, Michael R. McDevitt1, Deborah A. Mulford1, Neeta Pandit-Taskar1, Chaitanya R. Divgi1, Katherine S. Panageas1, Mark L. Heaney1, Suzanne Chanel1, Alfred Morgenstern2, George Sgouros1, Steven M. Larson1, David A. Scheinberg1, and Joseph G. Jurcic1 Abstract Purpose: Lintuzumab (HuM195), a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest single-agent activity against acute myeloid leukemia (AML). To increase the potency of the antibody without the nonspecific cytotoxicity associated with β-emitters, the α-particle–emitting ra- dionuclide bismuth-213 (213Bi) was conjugated to lintuzumab. This phase I/II trial was conducted to determine the maximum tolerated dose (MTD) and antileukemic effects of 213Bi-lintuzumab, the first targeted α-emitter, after partially cytoreductive chemotherapy. Experimental Design: Thirty-one patients with newly diagnosed (n = 13) or relapsed/refractory (n = 18) AML (median age, 67 years; range, 37-80) were treated with cytarabine (200 mg/m2/d) for 5 days followed by 213Bi-lintuzumab (18.5-46.25 MBq/kg). Results: The MTD of 213Bi-lintuzumab was 37 MB/kg; myelosuppression lasting >35 days was dose limiting. Extramedullary toxicities were primarily limited to grade ≤2 events, including infusion-related reactions. Transient grade 3/4 liver function abnormalities were seen in five patients (16%). Treatment- related deaths occurred in 2 of 21 (10%) patients who received the MTD. -
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. -
Advances and Limitations of Antibody Drug Conjugates for Cancer
biomedicines Review Advances and Limitations of Antibody Drug Conjugates for Cancer Candice Maria Mckertish and Veysel Kayser * Sydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; [email protected] * Correspondence: [email protected]; Tel.: +61-2-9351-3391 Abstract: The popularity of antibody drug conjugates (ADCs) has increased in recent years, mainly due to their unrivalled efficacy and specificity over chemotherapy agents. The success of the ADC is partly based on the stability and successful cleavage of selective linkers for the delivery of the payload. The current research focuses on overcoming intrinsic shortcomings that impact the successful devel- opment of ADCs. This review summarizes marketed and recently approved ADCs, compares the features of various linker designs and payloads commonly used for ADC conjugation, and outlines cancer specific ADCs that are currently in late-stage clinical trials for the treatment of cancer. In addition, it addresses the issues surrounding drug resistance and strategies to overcome resistance, the impact of a narrow therapeutic index on treatment outcomes, the impact of drug–antibody ratio (DAR) and hydrophobicity on ADC clearance and protein aggregation. Keywords: antibody drug conjugates; drug resistance; linkers; payloads; therapeutic index; target specific; ADC clearance; protein aggregation Citation: Mckertish, C.M.; Kayser, V. Advances and Limitations of Antibody Drug Conjugates for 1. Introduction Cancer. Biomedicines 2021, 9, 872. Conventional cancer therapy often entails a low therapeutic window and non-specificity https://doi.org/10.3390/ of chemotherapeutic agents that consequently affects normal cells with high mitotic rates biomedicines9080872 and provokes an array of adverse effects, and in some cases leads to drug resistance [1]. -
Patient Resource Free
PATIENT RESOURCE FREE Third Edition CancerUnderstanding Immunotherapy Published in partnership with CONTENT REVIEWED BY A DISTINGUISHED PRP MEDICAL PATIENT ADVISORY RESOURCE BOARD PUBLISHING® Understanding TABLE OF CONTENTS Cancer Immunotherapy Third Edition IN THIS GUIDE 1 Immunotherapy Today 2 The Immune System 4 Immunotherapy Strategies 6 Melanoma Survivor Story: Jane McNee Chief Executive Officer Mark A. Uhlig I didn’t look sick, so I didn’t want to act sick. Publisher Linette Atwood Having and treating cancer is only one part of your life. Co-Editor-in-Chief Charles M. Balch, MD, FACS Jane McNee, melanoma survivor Co-Editor-in-Chief Howard L. Kaufman, MD, FACS Senior Vice President Debby Easum 7 The Road to Immunotherapy Vice President, Operations Leann Sandifar 8 Cancer Types Managing Editor Lori Alexander, MTPW, ELS, MWC™ 14 Side Effects Senior Editors Dana Campbell Colleen Scherer 15 Glossary Graphic Designer Michael St. George 16 About Clinical Trials Medical Illustrator Todd Smith 16 Cancer Immunotherapy Clinical Trials by Disease Production Manager Jennifer Hiltunen 35 Support & Financial Resources Vice Presidents, Amy Galey Business Development Kathy Hungerford 37 Notes Stephanie Myers Kenney Account Executive Melissa Amaya Office Address 8455 Lenexa Drive CO-EDITORS-IN-CHIEF Overland Park, KS 66214 For Additional Information [email protected] Charles M. Balch, MD, FACS Advisory Board Visit our website at Professor of Surgery, The University of Texas PatientResource.com to read bios of MD Anderson Cancer Center our Medical and Patient Advisory Board. Editor-in-Chief, Patient Resource LLC Editor-in-Chief, Annals of Surgical Oncology Past President, Society of Surgical Oncology For Additional Copies: To order additional copies of Patient Resource Cancer Guide: Understanding Cancer Immunotherapy, Howard L. -
IMGN779, a Novel CD33-Targeting Antibody-Drug Conjugate with DNA Alkylating Activity, Exhibits Potent Antitumor Activity in Models of AML
Author Manuscript Published OnlineFirst on March 27, 2018; DOI: 10.1158/1535-7163.MCT-17-1077 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. IMGN779, a Novel CD33-Targeting Antibody-Drug Conjugate with DNA Alkylating Activity, Exhibits Potent Antitumor Activity in Models of AML Yelena Kovtun1*, Paul Noordhuis2*, Kathleen R. Whiteman1, Krystal Watkins1, Gregory E. Jones1, Lauren Harvey1, Katharine C. Lai1, Scott Portwood3, Sharlene Adams1, Callum M. Sloss1, Gerrit Jan Schuurhuis2, Gert Ossenkoppele2, Eunice S. Wang3, and Jan Pinkas1 1ImmunoGen, Inc., Waltham, Massachusetts. 2Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands. 3Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York *These authors contributed equally to the work Running Title: Preclinical activity of IMGN779 in AML Corresponding author: Yelena Kovtun, ImmunoGen Inc., 830 Winter St, Waltham, MA 02451. Phone: (781) 895-0716; Fax: (781) 895-0611; Email: [email protected] Potential conflict of interests: E.S. Wang received financial support from, and has served on an advisory board for, Immunogen Inc. There are no other competing interests to declare. 1 Downloaded from mct.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 27, 2018; DOI: 10.1158/1535-7163.MCT-17-1077 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract The myeloid differentiation antigen CD33 has long been exploited as a target for antibody-based therapeutic approaches in acute myeloid leukemia (AML). Validation of this strategy was provided with the approval of the CD33-targeting antibody-drug conjugate (ADC) gemtuzumab ozogamicin in 2000; the clinical utility of this agent has however been hampered by safety concerns. -
Guide to Treatment Role of Antibodies in Acute Leukemia: Focus on Transplant-Eligible Populations
PRACTICE AID Guide to Treatment Role of Antibodies in Acute Leukemia: Focus on Transplant-Eligible Populations Acute Myeloid Leukemia DRUG STATUS TARGET DOSE EU EMA approved: In combination with daunorubicin and Induction: 3 mg/m2 (up to 5 mg/m2 in EU and 4.5 mg/m2 in US) cytarabine for pts aged ≥15 y with previously untreated, on d 1, 4, and 7 in combination with daunorubicin and cytarabine de novo CD33+ AML, except APL CD33 Consolidation: 3 mg/m2 (up to 5 mg/m2 in EU and 4.5 mg/m2 in US) Gemtuzumab US FDA approved: Newly diagnosed CD33+ AML in adults and 1,2 on d 1 in combination with daunorubicin and cytarabine ozogamicin pediatric pts aged ≥1 month; R/R CD33+ AML in adults and Please consult label for single-agent dosing and dosing in R/R AML. pediatric pts aged 2 y Phase 3 SIERRA study CD45 Adults aged ≥55 y with active R/R AML, adequate organ Dosimetry directed (SIERRA study) Iomab-B3 function, and related/unrelated matched donor (BC8 mAb linked to radioisotope iodine-131) Acute Lymphoblastic Leukemia EU EMA approved: Adults with R/R CD22+ B-cell ALL; adults Cycle 1 dose: 0.8 mg/m2 on d 1; 0.5 mg/m2 on days 8 and 15 for 21 d 2 Inotuzumab with Ph+ R/R B-cell ALL who failed treatment with at least one TKI CD22 Patients in CR/CRi: 0.5 mg/m on days 1, 8, and 15 for 28 d ozogamicin4,5 US FDA approved: Adults with R/R CD22+ B-cell ALL Patients not in CR/CRi: Use cycle 1 dose for 28 d EU Dose: By patient’s weight (≥45 kg = 9 mcg/d on d 1-7 and 28 mcg/d on EU EMA approved: Adults with B-cell ALL who are in d 8-28; <45 kg = 5 mcg/m2/d on -
Whither Radioimmunotherapy: to Be Or Not to Be? Damian J
Published OnlineFirst April 20, 2017; DOI: 10.1158/0008-5472.CAN-16-2523 Cancer Perspective Research Whither Radioimmunotherapy: To Be or Not To Be? Damian J. Green1,2 and Oliver W. Press1,2,3 Abstract Therapy of cancer with radiolabeled monoclonal antibodies employing multistep "pretargeting" methods, particularly those has produced impressive results in preclinical experiments and in utilizing bispecific antibodies, have greatly enhanced the thera- clinical trials conducted in radiosensitive malignancies, particu- peutic efficacy of radioimmunotherapy and diminished its toxi- larly B-cell lymphomas. Two "first-generation," directly radiola- cities. The dramatically improved therapeutic index of bispecific beled anti-CD20 antibodies, 131iodine-tositumomab and 90yttri- antibody pretargeting appears to be sufficiently compelling to um-ibritumomab tiuxetan, were FDA-approved more than a justify human clinical trials and reinvigorate enthusiasm for decade ago but have been little utilized because of a variety of radioimmunotherapy in the treatment of malignancies, particu- medical, financial, and logistic obstacles. Newer technologies larly lymphomas. Cancer Res; 77(9); 1–6. Ó2017 AACR. "To be, or not to be, that is the question: Whether 'tis nobler in the pembrolizumab (anti-PD-1), which are not directly cytotoxic mind to suffer the slings and arrows of outrageous fortune, or to take for cancer cells but "release the brakes" on the immune system, arms against a sea of troubles, And by opposing end them." Hamlet. allowing cytotoxic T cells to be more effective at recognizing –William Shakespeare. and killing cancer cells. Outstanding results have already been demonstrated with checkpoint inhibiting antibodies even in far Introduction advanced refractory solid tumors including melanoma, lung cancer, Hodgkin lymphoma and are under study for a multi- Impact of monoclonal antibodies on the field of clinical tude of other malignancies (4–6). -
TRUNCATED EPIDERIMAL GROWTH FACTOR RECEPTOR (Egfrt)
(19) TZZ _T (11) EP 2 496 698 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07K 14/71 (2006.01) C12N 9/12 (2006.01) 09.01.2019 Bulletin 2019/02 (86) International application number: (21) Application number: 10829041.2 PCT/US2010/055329 (22) Date of filing: 03.11.2010 (87) International publication number: WO 2011/056894 (12.05.2011 Gazette 2011/19) (54) TRUNCATED EPIDERIMAL GROWTH FACTOR RECEPTOR (EGFRt) FOR TRANSDUCED T CELL SELECTION VERKÜRZTER REZEPTOR FÜR DEN EPIDERMALEN WACHSTUMSFAKTOR-REZEPTOR ZUR AUSWAHL UMGEWANDELTER T-ZELLEN RÉCEPTEUR DU FACTEUR DE CROISSANCE DE L’ÉPIDERME TRONQUÉ (EGFRT) POUR LA SÉLECTION DE LYMPHOCYTES T TRANSDUITS (84) Designated Contracting States: • LI ET AL.: ’Structural basis for inhibition of the AL AT BE BG CH CY CZ DE DK EE ES FI FR GB epidermal growth factor receptor by cetuximab.’ GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO CANCER CELL vol. 7, 2005, pages 301 - 311, PL PT RO RS SE SI SK SM TR XP002508255 • CHAKRAVERTY ET AL.: ’An inflammatory (30) Priority: 03.11.2009 US 257567 P checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral (43) Date of publication of application: tissues.’ JEM vol. 203, no. 8, 2006, pages 2021 - 12.09.2012 Bulletin 2012/37 2031, XP008158914 • POWELL ET AL.: ’Large-Scale Depletion of (73) Proprietor: City of Hope CD25+ Regulatory T Cells from Patient Duarte, CA 91010 (US) Leukapheresis Samples.’ J IMMUNOTHER vol. 28, no. -
Multiple Myeloma and Engineered Cell Therapy
Multiple Myeloma and Engineered Cell Therapy Sarah M. Larson, MD Assistant Professor of Medicine September 2018 Spectrum of Disease Morgan GJ Nat Cancer Rev 2012 SMM: Janssen SMM3001 • Patients randomized to dara sc vs active monitoring •Study duration 8 years • Primary endpoint PFS • Prior SMM treatment is an exclusion • NCT03301220 Van de Donk NWCJ Immunol Rev 2016 Multiple Myeloma • Second most common heme malignancy • 33,000 new cases 2017 • >100,000 people with multiple myeloma • Increasing number of patients • Incidence • Improved survival SEER database Treatment Treatment of Initial Consolidation/ ASCT relapsed Therapy Maintenance disease Supportive Care Minimal Residual Disease (MRD) Undetectable MRD: The Goal of Frontline Therapy? PFS OS Landgren O BMT 2016 IFM2009 • Newly diagnosed patients eligible for transplant • Patients <65 years of age PFS 50 mos (p<0.001) CR 59% Transplant MRD neg 79% (p<0.001) R 2 cycles A Len Main RVD N 3 D Cycles O RVD M PFS 36 mos I CR 48% Z MRD neg 65% E 5 Cycles D RVD Len Main Attal M NEJM 2017 Response at Each Treatment Phase Treatment Arm Induction Consolidation Maintenance (%) (%) (%) RVD 45 69 76 Transplant 47 78 85 Attal M NEJM 2017 Conclusions • Transplant remains a standard therapy • Delayed transplant is reasonable • Collection and storage of stem cell frequently not covered • Following second line of treatment • Trials to improve the transplant course Stem Cell Mobilization Trial • BL-8040 Phase III, randomized, double-blinded, placebo controlled trial of BL-8040 and G-CSF vs G- CSF and -
Actinium Pharmaceuticals, Inc
Actinium Pharmaceuticals, Inc. ATNM: NYSE AMERICAN November 2019 Disclaimer and Safe Harbor The information presented herein contains express and implied forward-looking statements regarding the current intentions, expectations, estimates, opinions and beliefs of Actinium Pharmaceuticals, Inc. (“Actinium”) that are not historical facts. These forward- looking statements include statements regarding Actinium’s expectations for its product candidates (including their therapeutic and commercial potential, anticipated future development activities, anticipated timing of development activities, including initiation of clinical trials and presentations of clinical data and the indications Actinium and its collaborators plan to pursue), future results of operations and financial position, business strategy, strategic collaborations, any royalty or milestone payments and Actinium’s ability to obtain and maintain intellectual property protection for its product candidates. Such forward-looking statements may be identified by words such as “believes”, “may”, “will”, “expects”, “endeavors”, “anticipates”, “intends”, “plans”, “estimates”, “projects”, “should”, “objective” and variations of such words and similar words. These statements are based on management’s current expectations and are subject to risks and uncertainties that may cause actual results to differ materially from the anticipated or estimated future results, including the risks and uncertainties associated with preliminary study results varying from final results, estimates of potential -
2017 Immuno-Oncology Medicines in Development
2017 Immuno-Oncology Medicines in Development Adoptive Cell Therapies Drug Name Organization Indication Development Phase ACTR087 + rituximab Unum Therapeutics B-cell lymphoma Phase I (antibody-coupled T-cell receptor Cambridge, MA www.unumrx.com immunotherapy + rituximab) AFP TCR Adaptimmune liver Phase I (T-cell receptor cell therapy) Philadelphia, PA www.adaptimmune.com anti-BCMA CAR-T cell therapy Juno Therapeutics multiple myeloma Phase I Seattle, WA www.junotherapeutics.com Memorial Sloan Kettering New York, NY anti-CD19 "armored" CAR-T Juno Therapeutics recurrent/relapsed chronic Phase I cell therapy Seattle, WA lymphocytic leukemia (CLL) www.junotherapeutics.com Memorial Sloan Kettering New York, NY anti-CD19 CAR-T cell therapy Intrexon B-cell malignancies Phase I Germantown, MD www.dna.com ZIOPHARM Oncology www.ziopharm.com Boston, MA anti-CD19 CAR-T cell therapy Kite Pharma hematological malignancies Phase I (second generation) Santa Monica, CA www.kitepharma.com National Cancer Institute Bethesda, MD Medicines in Development: Immuno-Oncology 1 Adoptive Cell Therapies Drug Name Organization Indication Development Phase anti-CEA CAR-T therapy Sorrento Therapeutics liver metastases Phase I San Diego, CA www.sorrentotherapeutics.com TNK Therapeutics San Diego, CA anti-PSMA CAR-T cell therapy TNK Therapeutics cancer Phase I San Diego, CA www.sorrentotherapeutics.com Sorrento Therapeutics San Diego, CA ATA520 Atara Biotherapeutics multiple myeloma, Phase I (WT1-specific T lymphocyte South San Francisco, CA plasma cell leukemia www.atarabio.com