DOCSLIB.ORG

Antibody Drug Conjugates: Future Directions in Clinical and Translational Strategies to 2 Improve the Therapeutic Index

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Antibody Drug Conjugates: Future Directions in Clinical and Translational Strategies to 2 Improve the Therapeutic Index Author Manuscript Published OnlineFirst on April 12, 2019; DOI: 10.1158/1078-0432.CCR-19-0272 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 1 Antibody Drug Conjugates: Future Directions in Clinical and Translational Strategies to 2 Improve the Therapeutic Index 3 4 Authors: Steven Coats1, Marna Williams1, Benjamin Kebble1, Rakesh Dixit1, Leo Tseng1, Nai- 5 Shun Yao1, David A. Tice1, and Jean-Charles Soria1,2 6 7 Affiliations: 1AstraZeneca, Gaithersburg, MD, USA. 2University Paris-Sud, Orsay, France. 8 9 Running title: Advances in Antibody Drug Conjugate Clinical Development 10 11 Corresponding Author: Steven Coats 12 Research and Development Oncology 13 AstraZeneca 14 1 MedImmune Way 15 Gaithersburg, MD 20878 16 Email: [email protected] 17 18 DISCLOSURE OF POTENTIAL CONFLICT OF INTEREST 19 All authors are employees of AstraZeneca and hold stock/stock options in AstraZeneca. Dr. 20 Soria also holds stock/stock options in Gritstone. Over the last 5 years, Dr. Soria has received 21 consultancy fees from AstraZeneca, Astex, Clovis, GSK, GamaMabs, Lilly, MSD, Mission 22 Therapeutics, Merus, Pfizer, PharmaMar, Pierre Fabre, Roche/Genentech, Sanofi, Servier, 23 Symphogen, and Takeda. 24 25 26 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 12, 2019; DOI: 10.1158/1078-0432.CCR-19-0272 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 2 27 ABSTRACT 28 Since the first approval of gemtuzumab ozogamicin (Mylotarg; CD33 targeted), 2 additional 29 antibody drug conjugates (ADCs)—brentuximab vedotin (Adcetris; CD30 targeted) and 30 inotuzumab ozogamicin (Besponsa; CD22 targeted)—have been approved for hematologic 31 cancers and 1 ADC, trastuzumab emtansine (Kadcyla; HER2 targeted), has been approved to 32 treat breast cancer. Despite a clear clinical benefit being demonstrated for all 4 approved ADCs, 33 the toxicity profiles are comparable to those of standard-of-care chemotherapeutics, with dose- 34 limiting toxicities associated with the mechanism of activity of the cytotoxic warhead. However, 35 the enthusiasm to develop ADCs has not been dampened; approximately 80 ADCs are in 36 clinical development in nearly 600 clinical trials, and 2 to 3 novel ADCs are likely to be approved 37 within the next few years. While the promise of a more targeted chemotherapy with less toxicity 38 has not yet been realized with ADCs, improvements in technology combined with a wealth of 39 clinical data are helping to shape the future development of ADCs. In this review we discuss the 40 clinical and translational strategies associated with improving the therapeutic index for ADCs. 41 42 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 12, 2019; DOI: 10.1158/1078-0432.CCR-19-0272 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 3 43 Introduction 44 Antibody drug conjugates (ADCs) were initially designed to leverage the exquisite specificity of 45 antibodies to deliver targeted potent chemotherapeutic agents with the intention of improving 46 the therapeutic index (the ratio between the toxic dose and the dose at which the drug becomes 47 effective; Figure 1) (1, 2). Unfortunately, the greatest challenge to date for developing ADCs is 48 a therapeutic index far narrower than expected (3-5). Of approximately 55 traditional ADCs for 49 which clinical development has been halted, we estimate that at least 23 have been 50 discontinued due to a poor therapeutic index; however, this is likely a conservative estimate 51 based on the availability of clinical data. A narrow therapeutic window limits the dose that can 52 be achieved, often resulting in toxic effects occurring before an ADC reaches its maximally 53 efficacious dose. Furthermore, these toxicities limit the number of dosing cycles that patients 54 can tolerate and often result in skipped doses, dose reductions, or study discontinuations (6, 7). 55 56 In this review we discuss clinical and translational strategies to improve the therapeutic index of 57 ADCs that are based on the latest clinical efficacy and safety data with next-generation 58 antibodies and warheads currently in development. While technology plays a crucial role in 59 expanding the therapeutic index of ADCs, we refer readers to several excellent reviews that 60 cover novel advancements in antibody, linker, and warhead technologies in significant depth (2, 61 3, 8, 9) 62 Overview of ADCs in Clinical Development 63 Four ADCs have been approved over the last 20 years (Figure 2A)(2). The first ADC approved 64 for clinical use was gemtuzumab ozogamicin (Mylotarg; CD33 targeted) for relapsed acute 65 myeloid leukemia in 2000 (10). In 2010, gemtuzumab ozogamicin was withdrawn from the US 66 market when a confirmatory trial showed that it was associated with a greater rate of fatal 67 toxicities vs standard-of-care chemotherapy (5.8% vs 0.8%) (10, 11). In 2017, gemtuzumab 68 ozogamicin was reapproved for relapsed/refractory acute myeloid leukemia after a phase 3 trial 69 with a fractionated dosing schedule lowered the peak serum concentration and improved the 70 safety profile, with a complete response rate of 26% (12). These clinical data demonstrate the 71 importance of understanding the relationship between the exposure, safety, and efficacy of 72 ADCs in clinical development. 73 Other ADCs that have been approved are brentuximab vedotin (Adcetris; CD30 targeted) (13) 74 and inotuzumab ozogamicin (Besponsa; CD22 targeted) (14), which were approved for Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 12, 2019; DOI: 10.1158/1078-0432.CCR-19-0272 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 4 75 hematologic malignancies, and trastuzumab emtansine (Kadcyla; HER2 targeted), which was 76 approved for breast cancer (15). Across phase 2 and 3 studies, response rates were 77 significantly higher in patients treated with ADCs than in those treated with standard intensive 78 chemotherapy (14, 16-18). 79 Clear clinical benefits have been demonstrated with all 4 approved ADCs; however, each has 80 reported toxicity profiles that are specific to its cytotoxic warhead and, therefore, they cannot be 81 differentiated from standard-of-care chemotherapies (13-15) in terms of safety. Regardless of 82 the obstacles, there is intense interest in developing ADCs—approximately 80 ADC candidates 83 are reportedly in clinical development, with nearly 600 clinical trials ongoing—and it is likely that 84 several new ADCs will be approved over the next few years (Figure 2A) (19) led by the recent 85 Biologics License Application filing for polatuzumab vedotin (CD79b targeted) in 86 relapsed/refractory DLBCL. Although ADCs have not yet delivered on the promise of a more- 87 targeted chemotherapy with an improved toxicity profile, new strategies may prove crucial to 88 improving the therapeutic index of ADCs (4, 20, 21). These strategies include the use of 89 warheads with lower potencies and alternative mechanisms of activity as described below. 90 Two examples of ADCs in clinical development that use warheads that inhibit topoisomerase I 91 activity include trastuzumab deruxtecan targeting HER2 in breast and gastric cancers and 92 sacituzumab govitecan targeting Trop2 in breast and lung cancers (22, 23). A Biologics License 93 Application has been filed for sacituzumab govitecan for metastatic triple-negative breast 94 cancer, and trastuzumab deruxtecan is currently in multiple late-stage pivotal clinical trials. The 95 clinical data for trastuzumab deruxtecan from an ongoing phase 1 study in HER2-high 96 metastatic breast cancer (post trastuzumab emtansine) showed an ORR of 55% with median 97 progression-free survival not reached (Table 1). Updated recent data have shown a median 98 duration of response of 20.7 months, which compares favorably with trastuzumab emtansine, 99 which, in a pivotal study in HER2-high metastatic breast cancer, showed an ORR of 43.6%, a 100 median progression-free survival of 9.6 months, and a median duration of response of 12.6 101 months (22). In a phase 1 trial in third-line triple-negative breast cancer, sacituzumab govitecan 102 demonstrated an ORR of 31% and a median progression-free survival of 5.5 months (Table 1). 103 In this trial, sacituzumab govitecan was dosed at 10 mg/kg on days 1 and 8 every 21 days and 104 showed improved tolerability compared with other ADCs targeting Trop2 such as PF-06664178, 105 which had a maximum tolerated dose of 2.4 mg/kg, showed limited efficacy, and was terminated 106 due to high toxicity (23). 107 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 12, 2019; DOI: 10.1158/1078-0432.CCR-19-0272 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 5 108 The results from this phase 1 trial with sacituzumab govitecan provide an example of the 109 importance of matching the right drug to the right target for the right patient. Even when 110 comparing ADCs that use the same antibody against the same target in a similar patient 111 population, trastuzumab emtansine and trastuzumab deruxtecan have demonstrated clinical 112 activity, whereas a trastuzumab tesirine conjugate (ADCT-502) was recently discontinued due 113 to a narrow therapeutic index (24). HER2 is known to be expressed in several normal tissues 114 such as in the lung and the gastrointestinal tract (25). This creates 2 potential problems for an 115 ADC. First, the normal expression of the antigen creates a sink for the ADC that must be 116 overcome to maximize exposure to the tumor (26, 27).
Load more

Recommended publications
  • Press Release
    Press Release Daiichi Sankyo and AstraZeneca Announce Global Development and Commercialization Collaboration for Daiichi Sankyo’s HER2 Targeting Antibody Drug Conjugate [Fam-] Trastuzumab Deruxtecan (DS-8201) Collaboration combines Daiichi Sankyo’s scientific and technological excellence with AstraZeneca’s global experience and resources in oncology to accelerate and expand the potential of [fam-] trastuzumab deruxtecan as monotherapy and combination therapy across a spectrum of HER2 expressing cancers AstraZeneca to pay Daiichi Sankyo up to $6.90 billion in total consideration, including $1.35 billion upfront payment and up to an additional $5.55 billion contingent upon achievement of future regulatory and sales milestones as well as other contingencies Companies to share equally development and commercialization costs as well as profits worldwide from [fam-] trastuzumab deruxtecan with Daiichi Sankyo maintaining exclusive rights in Japan Daiichi Sankyo is expected to book sales in U.S., certain countries in Europe, and certain other markets where Daiichi Sankyo has affiliates; AstraZeneca is expected to book sales in all other markets worldwide, including China, Australia, Canada and Russia Tokyo, Munich and Basking Ridge, NJ – (March 28, 2019) – Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) announced today that it has entered into a global development and commercialization agreement with AstraZeneca for Daiichi Sankyo’s lead antibody drug conjugate (ADC), [fam-] trastuzumab deruxtecan (DS-8201), currently in pivotal development for multiple HER2 expressing cancers including breast and gastric cancer, and additional development in non-small cell lung and colorectal cancer. Daiichi Sankyo and AstraZeneca will jointly develop and commercialize [fam-] trastuzumab deruxtecan as a monotherapy or a combination therapy worldwide, except in Japan where Daiichi Sankyo will maintain exclusive rights.
    [Show full text]
  • Fam-Trastuzumab Deruxtecan-Nxki Submitted by Daiichi
    Dan Liang, PharmD Associate Director, Medical Information & Education Daiichi Sankyo, Inc. 211 Mount Airy Road Basking Ridge, NJ 07920 Phone: 908-992-7054 Email: [email protected] Date of request: July 9, 2020 NCCN Panel: Colon Cancer and Rectal Cancer On behalf of Daiichi Sankyo, Inc. and AstraZeneca Pharmaceuticals LP, I respectfully request the NCCN Guideline Panel for Colon and Rectal Cancers to review data from the clinical study1 in support of fam-trastuzumab deruxtecan-nxki, also known as T-DXd, as a monotherapy option for the treatment of patients with HER2-positive unresectable and/or metastatic colorectal cancer. Specific Changes: We respectfully ask the NCCN panel to consider the following: • COL-D1 through COL-D6 and REC-F1 through REC-F6, “Continuum of Care - Systemic Therapy for Advanced or Metastatic Disease” o Add “Fam-trastuzumab deruxtecan-nxki (HER2-positive and RAS and BRAF WT)” to the following: . COL-D1 and REC-F1: “Patient not appropriate for intensive therapy” . COL-D2 and REC-F2: “Previous oxaliplatin-based therapy without irinotecan” . COL-D3 and REC-F3: “Previous irinotecan-based therapy without oxaliplatin” . COL-D4 and REC-F4: “Previous treatment with oxaliplatin and irinotecan” . COL-D5 and REC-F5: “Previous therapy without irinotecan or oxaliplatin” . COL-D6 and REC-F6: “FOLFOX or CAPEOX or (FOLFOX or CAPEOX) + bevacizumab” • COL-D11 and REC-F11, “Systemic Therapy for Advanced or Metastatic Disease – Chemotherapy Regimens” o Add “Fam-trastuzumab deruxtecan-nxki 6.4 mg/kg IV on Day 1, cycled every 21 days” with a footnote: “fam-trastuzumab deruxtecan-nxki is approved for metastatic HER2-positive breast cancer at a different dose of 5.4 mg/kg IV on Day 1, cycled every 21 days” FDA Clearance: ENHERTU (fam-trastuzumab deruxtecan-nxki) is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.
    [Show full text]
  • Antibody–Drug Conjugates
    Published OnlineFirst April 12, 2019; DOI: 10.1158/1078-0432.CCR-19-0272 Review Clinical Cancer Research Antibody–Drug Conjugates: Future Directions in Clinical and Translational Strategies to Improve the Therapeutic Index Steven Coats1, Marna Williams1, Benjamin Kebble1, Rakesh Dixit1, Leo Tseng1, Nai-Shun Yao1, David A. Tice1, and Jean-Charles Soria1,2 Abstract Since the first approval of gemtuzumab ozogamicin nism of activity of the cytotoxic warhead. However, the (Mylotarg; Pfizer; CD33 targeted), two additional antibody– enthusiasm to develop ADCs has not been dampened; drug conjugates (ADC), brentuximab vedotin (Adcetris; Seat- approximately 80 ADCs are in clinical development in tle Genetics, Inc.; CD30 targeted) and inotuzumab ozogami- nearly 600 clinical trials, and 2 to 3 novel ADCs are likely cin (Besponsa; Pfizer; CD22 targeted), have been approved for to be approved within the next few years. While the hematologic cancers and 1 ADC, trastuzumab emtansine promise of a more targeted chemotherapy with less tox- (Kadcyla; Genentech; HER2 targeted), has been approved to icity has not yet been realized with ADCs, improvements treat breast cancer. Despite a clear clinical benefit being dem- in technology combined with a wealth of clinical data are onstrated for all 4 approved ADCs, the toxicity profiles are helping to shape the future development of ADCs. In this comparable with those of standard-of-care chemotherapeu- review, we discuss the clinical and translational strategies tics, with dose-limiting toxicities associated with the mecha- associated with improving the therapeutic index for ADCs. Introduction in antibody, linker, and warhead technologies in significant depth (2, 3, 8, 9). Antibody–drug conjugates (ADC) were initially designed to leverage the exquisite specificity of antibodies to deliver targeted potent chemotherapeutic agents with the intention of improving Overview of ADCs in Clinical Development the therapeutic index (the ratio between the toxic dose and the Four ADCs have been approved over the last 20 years (Fig.
    [Show full text]
  • Advances in Epidermal Growth Factor Receptor Specific Immunotherapy: Lessons to Be Learned from Armed Antibodies
    www.oncotarget.com Oncotarget, 2020, Vol. 11, (No. 38), pp: 3531-3557 Review Advances in epidermal growth factor receptor specific immunotherapy: lessons to be learned from armed antibodies Fleury Augustin Nsole Biteghe1,*, Neelakshi Mungra2,*, Nyangone Ekome Toung Chalomie4, Jean De La Croix Ndong5, Jean Engohang-Ndong6, Guillaume Vignaux7, Eden Padayachee8, Krupa Naran2,* and Stefan Barth2,3,* 1Department of Radiation Oncology and Biomedical Sciences, Cedars-Sinai Medical, Los Angeles, CA, USA 2Medical Biotechnology & Immunotherapy Research Unit, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa 3South African Research Chair in Cancer Biotechnology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa 4Sun Yat-Sen University, Zhongshan Medical School, Guangzhou, China 5Department of Orthopedic Surgery, New York University School of Medicine, New York, NY, USA 6Department of Biological Sciences, Kent State University at Tuscarawas, New Philadelphia, OH, USA 7Arctic Slope Regional Corporation Federal, Beltsville, MD, USA 8Department of Physiology, University of Kentucky, Lexington, KY, USA *These authors contributed equally to this work Correspondence to: Stefan Barth, email: [email protected] Keywords: epidermal growth factor receptor (EGFR); recombinant immunotoxins (ITs); targeted human cytolytic fusion proteins (hCFPs); recombinant antibody-drug conjugates (rADCs); recombinant antibody photoimmunoconjugates (rAPCs) Received: May 30, 2020 Accepted: August 11, 2020 Published: September 22, 2020 Copyright: © 2020 Biteghe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
    [Show full text]
  • 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).
    [Show full text]
  • B-Cell Targets to Treat Antibody-Mediated Rejection In
    Muro et al. Int J Transplant Res Med 2016, 2:023 Volume 2 | Issue 2 International Journal of Transplantation Research and Medicine Commentary: Open Access B-Cell Targets to Treat Antibody-Mediated Rejection in Transplantation Manuel Muro1*, Santiago Llorente2, Jose A Galian1, Francisco Boix1, Jorge Eguia1, Gema Gonzalez-Martinez1, Maria R Moya-Quiles1 and Alfredo Minguela1 1Immunology Service, University Clinic Hospital Virgen de la Arrixaca, Spain 2Nephrology Service, University Clinic Hospital Virgen de la Arrixaca, Spain *Corresponding author: Manuel Muro, PhD, Immunology Service, University Clinic Hospital “Virgen de la Arrixaca”, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain, Tel: 34-968-369599, E-mail: [email protected] Antibody-mediated rejection (AMR) in allograft transplantation APRIL (a proliferation-inducing ligand). These co-activation signals can be defined with a rapid increase in the levels of specific are required for B-cell differentiation into plasma cell and enhancing serological parameters after organ transplantation, presence of donor their posterior survival and are a key determinant of whether specific antibodies (DSAs) against human leukocyte antigen (HLA) developing B-cells will survive or die during the establishment molecules, blood group (ABO) antigens and/or endothelial cell of immuno-tolerance [5,6]. Important used agents commercially antigens (e.g. MICA, ECA, Vimentin, or ETAR) and also particular available are Tocilizumab (anti-IL6R) and Belimumab (BAFF). histological parameters [1,2]. If the AMR persists or progresses, the The receptors of BAFF and APRIL could also be important as treatment to eliminate the humoral component of acute rejection eventual targets, for example BAFF-R, TACI (transmembrane include three sequential steps: (a) steroid pulses, antibody removal activator and calcium modulator and cyclophyllin ligand interactor) (plasma exchange or immuno-adsorption) and high doses of and BCMA (B-cell maturation antigen).
    [Show full text]
  • Monoclonal Antibodies
    MONOCLONAL ANTIBODIES ALEMTUZUMAB ® (CAMPATH 1H ) I. MECHANISM OF ACTION Antibody-dependent lysis of leukemic cells following cell surface binding. Alemtuzumab is a recombinant DNA-derived humanized monoclonal antibody that is directed against surface glycoprotein CD52. CD52 is expressed on the surface of normal and malignant B and T lymphocytes, NK cells, monocytes, macrophages, a subpopulation of granulocytes, and tissues of the male reproductive system (CD 52 is not expressed on erythrocytes or hematopoietic stem cells). The alemtuzumab antibody is an IgG1 kappa with human variable framework and constant regions, and complementarity-determining regions from a murine monoclonal antibody (campath 1G). II. PHARMACOKINETICS Cmax and AUC show dose proportionality over increasing dose ranges. The overall average half-life is 12 days. Peak and trough levels of Campath rise during the first weeks of Campath therapy, and approach steady state by week 6. The rise in serum Campath concentration corresponds with the reduction in malignant lymphocytes. III. DOSAGE AND ADMINISTRATION Campath can be administered intravenously or subcutaneously. Intravenous: Alemtuzumab therapy should be initiated at a dose of 3 mg administered as a 2-hour IV infusion daily. When the 3 mg dose is tolerated (i.e., ≤ Grade 2 infusion related side effects), the daily dose should be escalated to 10mg and continued until tolerated (i.e., ≤ Grade 2 infusion related side effects). When the 10 mg dose is tolerated, the maintenance dose of 30 mg may be initiated. The maintenance dose of alemtuzumab is 30 mg/day administered three times a week on alternate days (i.e. Monday, Wednesday, and Friday), for up to 12 weeks.
    [Show full text]
  • Antibody-Drug Conjugates (Adcs) – Biotherapeutic Bullets
    Sean L Kitson Antibody-Drug Conjugates (ADCs) – Biotherapeutic bullets SEAN L KITSON*, DEREK J QUINN, THOMAS S MOODY, DAVID SPEED, WILLIAM WATTERS, DAVID ROZZELL *Corresponding author Almac, Department of Biocatalysis and Isotope Chemistry, 20 Seagoe Industrial Estate, Craigavon, BT63 5QD, United Kingdom (chimeric human-murine IgG1 targeting EGF receptor) and KEYWORDS panitumumab (human IgG2 targeting EGF receptor) for the Antibody-drug conjugate; ADC; monoclonal antibody; treatment of metastatic colorectal cancer (5). cancer; carbon-14; linker; immunotherapy. This technology of tailoring MAbs has been exploited to develop delivery systems for radionuclides to image and treat a variety of cancers (6). This led to the hypothesis that a ABSTRACT cancer patient would first receive a radionuclide antibody capable of imaging the tumour volume. The images of the Immunotherapies especially targeted towards oncology, tumour are obtained by using one or more combinations of based on antibody-drug conjugates (ADCs) have the following methods: planar imaging; single photon recently been boosted by the US Food and Drug emission computed tomography (SPECT) and positron Administration approval of Adcetris to treat Hodgkin’s emission tomography (PET) (7). These techniques can be lymphoma and Kadcyla for metastatic breast cancer. extended to hybrid imaging systems incorporating PET (or The emphasis of this article is to provide an overview of SPECT) with computed tomography (CT) or magnetic the design of ADCs in order to examine their ability to 30 resonance imaging (MRI) (8). find and kill tumour cells. A particular focus will be on the relationship between the cytotoxic drug, chemical The imaging process is first used to locate the precise position linker and the type of monoclonal antibody (MAb) used of the tumour and ascertain the appropriate level of the to make up the components of the ADC.
    [Show full text]
  • Genmab and Seattle Genetics Present Data from Tisotumab Vedotin Innovatv 204 Pivotal Trial in Recurrent Or Metastatic Cervical Cancer at ESMO Virtual Congress 2020
    Genmab and Seattle Genetics Present Data from Tisotumab Vedotin innovaTV 204 Pivotal Trial in Recurrent or Metastatic Cervical Cancer at ESMO Virtual Congress 2020 Media Release COPENHAGEN, Denmark and BOTHELL, Wash., 21 September 2020 • Data featured in late-breaking proffered paper oral presentation • Biologics license application submission planned to support accelerated approval pathway with the FDA Genmab A/S (Nasdaq: GMAB) and Seattle Genetics, Inc. (Nasdaq: SGEN) today presented data from the innovaTV 204 pivotal phase 2, single-arm clinical trial evaluating tisotumab vedotin as monotherapy in patients with previously treated recurrent and/or metastatic cervical cancer at the European Society for Medical Oncology (ESMO) Virtual Congress 2020. Patients had previously received a doublet chemotherapy and, if eligible, bevacizumab as first-line therapy. Results from the trial showed a 24 percent confirmed objective response rate (ORR) by independent central review with a median duration of response (DOR) of 8.3 months. The most common treatment-related adverse events (greater than or equal to 20 percent) included alopecia, epistaxis (nose bleeds), nausea, conjunctivitis, fatigue and dry eye. Tisotumab vedotin is an investigational antibody-drug conjugate (ADC) directed to tissue factor (TF), which is prevalent on solid tumors including cervical cancer and can promote tumor growth, angiogenesis and metastasis.1 Current therapies for previously treated recurrent and/or metastatic cervical cancer generally result in limited objective response rates of typically less than 15 percent with median overall survival ranging from 6.0 to 9.4 months.1-8 “Following resistance to or progression on first-line standard of care therapy, there are limited treatment options for women with metastatic cervical cancer,” said Robert L.
    [Show full text]
  • Summary of Utilization Management (UM) Program Changes May #2 2020
    Summary of Utilization Management (UM) Program Changes May #2 2020 Brand Name Generic Name Utilization Update Summary Type Effective Date Adakveo crizanlizumab Trial and failure or inadequate response, Update 8/01/2020 contraindication, or intolerance to one of the following: Hydroxyurea or L- glutamine (i.e., Endari) Oxbryta voxelotor Clarified age to 12 years or older Update 8/01/2020 Givlaari givosiran Removed requirement that patient will Update 8/01/2020 not be anticipating liver transplantation. Padcev enfortumab vedotin Patient has received prior treatment with Update 8/01/2020 one immune checkpoint inhibitors (CPI) in the neoadjuvant/adjuvant, locally advanced or metastatic setting, unless contraindicated: i) Programmed death receptor-1 (PD-1) inhibitor [e.g.,Opdivo (nivolumab), Keytruda (pembrolizumab)], or ii) Programmed death-ligand 1 (PD-L1) inhibitor [e.g., Tecentriq (atezolizumab), Imfinzi (durvalumab), Bavencio (avelumab)]. Absorica LD isotretinoin A new product that has the same Update 8/01/2020 requirements as Absorica: for patients who are unresponsive to conventional therapy, including oral antibiotics, and is prescribed by a dermatologist. Jatenzo testosterone New oral formulation of testosterone. Update 8/01/2020 undecanoate Requires confirmation of diagnosis, testosterone lab values, and trial of both a testosterone patch and generic testosterone gel that are on formulary. Triluron sodium hyaluronate This new product has been added to the Update 08/01/2020 prior authorization guideline with the other hyaluronic acid derivatives. Approval requires diagnosis of osteoarthritis of the knee, a trial of two oral or an oral and topical medication, and trial of a corticosteroid injection in the knee. The 2019 American College of Rheumatology Osteoarthritis Guidelines now recommend use of duloxetine and topical capsaicin for knee osteoarthritis, so we will be adding these as alternatives to the oral/topical medications for each drug in this group.
    [Show full text]
  • F. Gherlinzoni CD33: Gemtuzumab Ozogamicin
    1ST CUNEO CITY IMMUNOTHERAPY CONFERENCE 17-18 Maggio 2018 PASSIVE IMMUNOTHERAPY ANTIBODY-DRUG CONJUGATES GEMTUZUMAB OZOGAMICIN Do#. Filippo Gherlinzoni Direore Unità Operava Complessa di Ematologia Ospedale “Ca’ Foncello” - Treviso IL RIECCOLO Blood Reviews 28 (2014) 143–153 Contents lists available at ScienceDirect Blood Reviews journal homepage: www.elsevier.com/locate/blre REVIEW The past and future of CD33 as therapeutic target in acute myeloid leukemia a a,b a,b,c, George144 S. Laszlo , Elihu H. Estey , Roland B. Walter ⁎G.S. Laszlo et al. / Blood Reviews 28 (2014) 143–153 a Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA b Department of Medicine, Division of Hematology, University of Washington, Seattle, WA, USA c Department of Epidemiology, University of Washington, Seattle, WA, USA as cytokine-induced cellular proliferation [14,33]. Engagement with CD33 antibodies has similarly been shown to affect cytokine and article info abstract chemokine secretion by monocytes, although both increases [34] or Keywords: CD33 is a myeloid differentiation antigen with endocytic properties.decreases It is broadly[33] expressedhave on been acute myeloidobserved in vitro. Acute myeloid leukemia leukemia (AML) blasts and, possibly, some leukemic stem cells and has therefore been exploited as target for Antibody therapeutic antibodies for many years. The improved survival seen in many patients when the antibody-drug Antibody-drug conjugate conjugate, gemtuzumab ozogamicin, is added to conventional chemotherapy validates this approach. However, fi 2.3. Endocytic properties of CD33 Bispeci c antibody many attempts with unconjugated or conjugated antibodies have been unsuccessful, highlighting the challenges BiTE of targeting CD33 in AML.
    [Show full text]
  • Antibody–Drug Conjugates: the Last Decade
    pharmaceuticals Review Antibody–Drug Conjugates: The Last Decade Nicolas Joubert 1,* , Alain Beck 2 , Charles Dumontet 3,4 and Caroline Denevault-Sabourin 1 1 GICC EA7501, Equipe IMT, Université de Tours, UFR des Sciences Pharmaceutiques, 31 Avenue Monge, 37200 Tours, France; [email protected] 2 Institut de Recherche Pierre Fabre, Centre d’Immunologie Pierre Fabre, 5 Avenue Napoléon III, 74160 Saint Julien en Genevois, France; [email protected] 3 Cancer Research Center of Lyon (CRCL), INSERM, 1052/CNRS 5286/UCBL, 69000 Lyon, France; [email protected] 4 Hospices Civils de Lyon, 69000 Lyon, France * Correspondence: [email protected] Received: 17 August 2020; Accepted: 10 September 2020; Published: 14 September 2020 Abstract: An armed antibody (antibody–drug conjugate or ADC) is a vectorized chemotherapy, which results from the grafting of a cytotoxic agent onto a monoclonal antibody via a judiciously constructed spacer arm. ADCs have made considerable progress in 10 years. While in 2009 only gemtuzumab ozogamicin (Mylotarg®) was used clinically, in 2020, 9 Food and Drug Administration (FDA)-approved ADCs are available, and more than 80 others are in active clinical studies. This review will focus on FDA-approved and late-stage ADCs, their limitations including their toxicity and associated resistance mechanisms, as well as new emerging strategies to address these issues and attempt to widen their therapeutic window. Finally, we will discuss their combination with conventional chemotherapy or checkpoint inhibitors, and their design for applications beyond oncology, to make ADCs the magic bullet that Paul Ehrlich dreamed of. Keywords: antibody–drug conjugate; ADC; bioconjugation; linker; payload; cancer; resistance; combination therapies 1.
    [Show full text]