DOCSLIB.ORG

Preclinical Characterization of HPN536, a Trispecific, T-Cell− Activating Protein Construct for the Treatment of Mesothelin-Expressing Solid Tumors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Preclinical Characterization of HPN536, a Trispecific, T-Cell− Activating Protein Construct for the Treatment of Mesothelin-Expressing Solid Tumors Published OnlineFirst December 1, 2020; DOI: 10.1158/1078-0432.CCR-20-3392 CLINICAL CANCER RESEARCH | TRANSLATIONAL CANCER MECHANISMS AND THERAPY Preclinical Characterization of HPN536, a Trispecific, T-Cell–Activating Protein Construct for the Treatment of Mesothelin-Expressing Solid Tumors A C Mary Ellen Molloy1, Richard J. Austin1, Bryan D. Lemon1, Wade H. Aaron1, Vaishnavi Ganti1, Adrie Jones1, Susan D. Jones1, Kathryn L. Strobel1, Purbasa Patnaik1, Kenneth Sexton1, Laurie Tatalick1, Timothy Z. Yu1, Patrick A. Baeuerle1,2,3, Che-Leung Law1, and Holger Wesche1 ABSTRACT ◥ Purpose: Mesothelin (MSLN) is a glycophosphatidylinositol- ity, and half-life of HPN536 in in vitro assays, rodent models, and in linked tumor antigen overexpressed in a variety of malignancies, nonhuman primates (NHP). including ovarian, pancreatic, lung, and triple-negative breast can- Results: HPN536 binds to MSLN-expressing tumor cells and to cer. Early signs of clinical efficacy with MSLN-targeting agents CD3e on T cells, leading to T-cell activation and potent redirected have validated MSLN as a promising target for therapeutic inter- target cell lysis. A third domain of HPN536 binds to serum albumin vention, but therapies with improved efficacy are still needed to for extension of plasma half-life. In cynomolgus monkeys, HPN536 address the significant unmet medical need posed by MSLN- at doses ranging from 0.1 to 10 mg/kg demonstrated MSLN- expressing cancers. dependent pharmacologic activity, was well tolerated, and showed Experimental Design: We designed HPN536, a 53-kDa, tri- pharmacokinetics in support of weekly dosing in humans. specific, T-cell–activating protein-based construct, which binds to Conclusions: HPN536 is potent, is well tolerated, and exhibits MSLN-expressing tumor cells, CD3e on T cells, and to serum extended half-life in NHPs. It is currently in phase I clinical testing albumin. Experiments were conducted to assess the potency, activ- in patients with MSLN-expressing malignancies (NCT03872206). Introduction a tumor antigen, a sdAb specific for serum albumin for half-life extension, and a single-chain fragment variable (scFv) specific for the Redirection of cytotoxic T cells with bispecific antibody constructs CD3e subunit of the TCR complex (11). Their molecular size of 53 kDa for cancer therapy has been validated in the clinic (1–6). Blinatumo- is about one-third of that of an IgG. Binding of TriTACs to tumor mab is the first and thus far the only bispecific T-cell engager (BiTE) antigen and CD3e is monovalent, which minimizes off-target CD3e approved by the FDA (7). T-cell–engaging biologics function by clustering that can potentially lead to nonspecific T-cell activation. The forming an immunologic cytolytic synapse between cancer target cells absence of an Fc-gamma domain for half-life extension is functionally and T cells, which leads to target cell lysis independent of T-cell compensated by an albumin-binding domain. HPN424 (11) and receptor (TCR) specificity, peptide antigen presentation by HLA, and HPN536, the first two TriTACs are in phase I clinical testing in T-cell costimulation. Despite the clinical success of blinatumomab for hormone refractory prostate cancer and mesothelin (MSLN)-over- treating relapsed and refractory acute lymphoblastic leukemia, other expressing solid tumors, respectively. molecules, including BiTE antibodies, showed only limited activity in Human MSLN is produced as a 71-kDa precursor of 628 amino the treatment of solid tumors (8, 9). Their short plasma half-life acids, which is expressed as a glycophosphatidylinositol-linked cell required continuous intravenous infusion limiting their utility for surface glycoprotein. Its 31-kDa N-terminal domain is released as a most solid tumor indications. Novel designs for T-cell–engaging soluble protein, termed as the megakaryocyte potentiating factor antibodies aim at overcoming limitations of the first generation and (MPF), while the 40-kDa C-terminal domain remains attached to the are already being tested in clinical trials (10). plasma membrane as mature MSLN (12–14). MSLN expression on The Trispecific T-cell–Activating Construct (TriTAC) design has normal tissue is confined to the single-cell mesothelial layer covering been specifically developed to treat solid tumors (11). TriTACs consist the surface of tissues and organs of the pleural, pericardial, and of a single polypeptide chain aligning three humanized, antibody- peritoneal cavities (13, 15). MUC16/CA125 is a binding partner for derived binding domains: a single-domain antibody (sdAb) specific for MSLN, implicating a role for MSLN in cell adhesion (16, 17). However, the precise physiologic functions of MSLN have not been defined, and MSLN-knockout mice exhibit no detectable phenotype or develop- 1Harpoon Therapeutics, South San Francisco, California. 2MPM Capital, Cam- bridge, Massachusetts. 3Institute for Immunology, Ludwig-Maximilians Univer- mental abnormality (18). sity Munich, Planegg- Martinsried, Munich, Germany. MSLN is overexpressed in many malignancies, including ovarian cancer (13, 15, 19), pancreatic cancer (20, 21), non–small cell lung Note: Supplementary data for this article are available at Clinical Cancer – Research Online (http://clincancerres.aacrjournals.org/). cancer (22 26), triple-negative breast cancer (26, 27), and mesothe- lioma (28, 29). In triple-negative breast cancer (25) and in lung and Corresponding Author: Mary Ellen Molloy, Harpoon Therapeutics, 131 Oyster Point Boulevard, 300, South San Francisco, CA 94080. Phone: 773-318-0796; pancreatic adenocarcinomas (22, 23, 30), overexpression of MSLN E-mail: [email protected] correlates with poor prognosis. Differential expression of MSLN in cancer versus normal tissue has made it an attractive target for MSLN- Clin Cancer Res 2020;XX:XX–XX directed imaging agents and therapeutics (10, 31–33). A challenge in doi: 10.1158/1078-0432.CCR-20-3392 developing MSLN-directed therapeutics is the expression of MSLN on Ó2020 American Association for Cancer Research. normal mesothelial cells, potentially leading to dose-limiting toxicities. AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst December 1, 2020; DOI: 10.1158/1078-0432.CCR-20-3392 Molloy et al. loads, appropriate serial dilutions of known analyte concentrations, Translational Relevance and association and dissociation times were then fit globally to a one- Patients with mesothelin (MSLN)-overexpressing tumors, to-one binding model using Octet DataAnalysis 9.0 software. including ovarian, pancreatic, lung, and triple-negative breast cancer, have a high unmet clinical need. A number of MSLN- In vitro T-cell–dependent cell cytotoxicity and T-cell activation targeted therapeutics have been developed that show limited assays efficacy and safety in clinical trials. HPN536 is a novel, MSLN- T cells from healthy donors were purified from leukopaks (leuka- targeted, trispecific, T-cell–activating protein construct that can pheresis samples, StemCell Technologies) using EasySep Human potently redirect T cells to lyse tumor cells and was remarkably well T Cell Isolation Kits (StemCell Technologies, 17951) following the tolerated in nonhuman primates at single doses up to 10 mg/kg, manufacturer's instructions. All cancer cell lines were obtained from which is far above the expected therapeutic dose level. Our findings the ATCC, with the exception of OVCAR8 cells, which were obtained suggest that HPN536 has the potential for high clinical activity from the NCI (Bethesda, MD). Cell lines were passaged a maximum of and a wide therapeutic window. Its long serum half-life supports 36 times after being received from the ATCC. Cell line authentication once-weekly dosing in humans. Currently, HPN536 is the only and Mycoplasma testing were not performed. T-cell–dependent cell MSLN-targeting, T-cell–engaging biologic in clinical testing. cytotoxicity (TDCC) assays were performed as described previous- ly (35). Briefly, luciferase-expressing target cells and purified human T cells were seeded per well of a 384-well plate at a 10:1 T cell-to-target cell ratio. Target cell killing was assessed following incubation for fi o HPN536 speci cally redirects T cells for potent redirected lysis of 48 hours at 37 C and 5% CO2. Target cell viability was assessed by MSLN-expressing cancer cells with concomitant T-cell activation. In incubation with the SteadyGlo Reagent (Promega). Luminescence was three different mouse xenograft models, HPN536 induced durable measured using a PerkinElmer EnVision Detection System. Activated antitumor activity at very low doses. In cynomolgus monkeys, T cells were identified by CD69 and CD25 surface expression (BD HPN536 was well tolerated, showed a long serum half-life, and elicited Biosciences). Samples were analyzed on a FACSCelesta Flow Cyt- signs of target engagement on mesothelial structures. ometer (BD Biosciences). Flow cytometry data were processed using FlowJo v10 Software (FlowJo, LLC). Materials and Methods Binding of HPN536 on MSLN-expressing OVCAR and T cells Protein production Cultured cells were incubated with 1 mg/mL HPN536 or anti-GFP Sequences of TriTACs, sdAbs, and extracellular domains of target TriTAC (control) for 1 hour. Binding was detected using Alexa647- proteins fused to an Fc domain or a hexahistidine tag were cloned into anti-TriTAC antibody using a FACSCelesta Flow Cytometer (BD mammalian expression vector, pcDNA 3.4 (Invitrogen), preceded by a Biosciences).
Load more

Recommended publications
  • Taking up Cancer Immunotherapy Challenges: Bispecific Antibodies
    Review Taking up Cancer Immunotherapy Challenges: Bispecific Antibodies, the Path Forward? Joanie Del Bano 1,2,3,4,†, Patrick Chames 1,2,3,4, Daniel Baty 1,2,3,4 and Brigitte Kerfelec 1,2,3,4,*,† Received: 12 November 2015; Accepted: 18 December 2015; Published: 26 December 2015 Academic Editor: Christian Klein 1 Inserm, U1068, CRCM, Marseille F-13009, France; [email protected] (J.D.B.); [email protected] (P.C.); [email protected] (D.B.) 2 Aix-Marseille University, Marseille F-13284, France 3 CNRS, UMR7258, CRCM, Marseille F-13009, France 4 Institut Paoli-Calmettes, Marseille F-13009, France * Correspondence: [email protected]; Tel.: +33-491-828-833; Fax: +33-491-828-840 † These authors contributed equally to this work. Abstract: As evidenced by the recent approvals of Removab (EU, Trion Pharma) in 2009 and of Blincyto (US, Amgen) in 2014, the high potential of bispecific antibodies in the field of immuno-oncology is eliciting a renewed interest from pharmaceutical companies. Supported by rapid advances in antibody engineering and the development of several technological platforms such as Triomab or bispecific T cell engagers (BiTEs), the “bispecifics” market has increased significantly over the past decade and may occupy a pivotal space in the future. Over 30 bispecific molecules are currently in different stages of clinical trials and more than 70 in preclinical phase. This review focuses on the clinical potential of bispecific antibodies as immune effector cell engagers in the onco-immunotherapy field. We summarize current strategies targeting various immune cells and their clinical interests.
    [Show full text]
  • Engineered Technologies and Bioanalysis of Multispecific Antibody Formats
    Journal of Applied Bioanalysis openaccess http://dx.doi.org/10.17145/jab.20.005 REVIEW Engineered Technologies and Bioanalysis of multispecific Antibody Formats Marta Amaral, Soraya Hölper, Christian Lange, Jennifer Jung, Hanno Sjuts, Sandra Weil, Melanie Fischer, Katarina Rado�evi�, Ercole Rao* Sanofi R&D, Biologics Research. *Correspondence: Sanofi-Aventis Deutschland GmbH, R&D, Biologics Research, Industriepark Höchst, H812, 65926 Frankfurt am Main, Germany. Phone: +49 6930515147. Email: [email protected] Citation: Amaral M, Hölper S, Lange C, Jung J, Sjuts H, Weil S, Fischer M, Rado�evic K, Rao E. Engineered Technologies and Bioanalysis of multispecific ABSTRACT antibody formats. J Appl Bioanal 6(1), The idea of designing multispecific antibodies capable of simultaneously 26-51 (2020). engaging two or more epitopes on the same or different antigens was developed more than 50 years ago. However, the molecular complexity of such Editor: molecules may pose significant challenges for their development and clinical Dr. Lin-zhi Chen, Boehringer use. Particularly challenging is to obtain the correctly assembled combination of Ingelheim Pharmaceuticals Inc., different polypeptide chains, which places significant demand on downstream Ridgefield, CT 06877, USA. process development, analytical characterization and control strategy. Here, we review the progress made in protein engineering to force the correct assembly of Received: July 29, 2019. different heavy and light chains, as well as upstream and downstream processes Revised: September 13, 2019. currently applied to control generation of unwanted byproduct species. We Accepted: September 16, 2019. cover in-depth the analytical methods available to characterize such complex molecules, focusing on mispairing analysis and functional characterization.
    [Show full text]
  • Ep 3178848 A1
    (19) TZZ¥__T (11) EP 3 178 848 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 14.06.2017 Bulletin 2017/24 C07K 16/28 (2006.01) A61K 39/395 (2006.01) C07K 16/30 (2006.01) (21) Application number: 15198715.3 (22) Date of filing: 09.12.2015 (84) Designated Contracting States: (72) Inventor: The designation of the inventor has not AL AT BE BG CH CY CZ DE DK EE ES FI FR GB yet been filed GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (74) Representative: Cueni, Leah Noëmi et al Designated Extension States: F. Hoffmann-La Roche AG BA ME Patent Department Designated Validation States: Grenzacherstrasse 124 MA MD 4070 Basel (CH) (71) Applicant: F. Hoffmann-La Roche AG 4070 Basel (CH) (54) TYPE II ANTI-CD20 ANTIBODY FOR REDUCING FORMATION OF ANTI-DRUG ANTIBODIES (57) The present invention relates to methods of treating a disease, and methods for reduction of the formation of anti-drug antibodies (ADAs) in response to the administration of a therapeutic agent comprising administration of a Type II anti-CD20 antibody, e.g. obinutuzumab, to the subject prior to administration of the therapeutic agent. EP 3 178 848 A1 Printed by Jouve, 75001 PARIS (FR) EP 3 178 848 A1 Description Field of the Invention 5 [0001] The present invention relates to methods of treating a disease, and methods for reduction of the formation of anti-drug antibodies (ADAs) in response to the administration of a therapeutic agent.
    [Show full text]
  • Overcoming Challenges for CD3-Bispecific Antibody Therapy In
    cancers Review Overcoming Challenges for CD3-Bispecific Antibody Therapy in Solid Tumors Jim Middelburg 1 , Kristel Kemper 2, Patrick Engelberts 2 , Aran F. Labrijn 2 , Janine Schuurman 2 and Thorbald van Hall 1,* 1 Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; [email protected] 2 Genmab, 3584 CT Utrecht, The Netherlands; [email protected] (K.K.); [email protected] (P.E.); [email protected] (A.F.L.); [email protected] (J.S.) * Correspondence: [email protected]; Tel.: +31-71-5266945 Simple Summary: CD3-bispecific antibody therapy is a form of immunotherapy that enables soldier cells of the immune system to recognize and kill tumor cells. This type of therapy is currently successfully used in the clinic to treat tumors in the blood and is under investigation for tumors in our organs. The treatment of these solid tumors faces more pronounced hurdles, which affect the safety and efficacy of CD3-bispecific antibody therapy. In this review, we provide a brief status update of this field and identify intrinsic hurdles for solid cancers. Furthermore, we describe potential solutions and combinatorial approaches to overcome these challenges in order to generate safer and more effective therapies. Abstract: Immunotherapy of cancer with CD3-bispecific antibodies is an approved therapeutic option for some hematological malignancies and is under clinical investigation for solid cancers. However, the treatment of solid tumors faces more pronounced hurdles, such as increased on-target off-tumor toxicities, sparse T-cell infiltration and impaired T-cell quality due to the presence of an Citation: Middelburg, J.; Kemper, K.; immunosuppressive tumor microenvironment, which affect the safety and limit efficacy of CD3- Engelberts, P.; Labrijn, A.F.; bispecific antibody therapy.
    [Show full text]
  • Tocilizumab, but Not Dexamethasone, Prevents CRS Without Affecting
    Open access Short report Tocilizumab, but not dexamethasone, J Immunother Cancer: first published as 10.1136/jitc-2020-000621 on 30 May 2020. Downloaded from prevents CRS without affecting antitumor activity of bispecific antibodies 1,2,3,4 1,2 1,2 3,4 Joseph Kauer , Sebastian Hörner, Lukas Osburg, Stefanie Müller, Melanie Märklin,3,4 Jonas S Heitmann,3,4 Latifa Zekri,1,2 Hans- Georg Rammensee,1,2,3 Helmut R Salih,3,4 Gundram Jung1,2 To cite: Kauer J, Hörner S, ABSTRACT However, a recent publication reports inhi- Osburg L, et al. Tocilizumab, but Bispecific antibodies (bsAb) and chimeric antigen receptor bition of bsAb-mediated T cell activation and not dexamethasone, prevents (CAR) T cells allow for antibody guided recruitment of T cells CRS without affecting antitumor tumor cell killing by dexamethasone during against tumors. Both are successfully used for treatment of 6 activity of bispecific antibodies. long- term stimulation. Moreover, steroid CD19 expressing leukemias, but may cause cytokine release Journal for ImmunoTherapy medication did not significantly increase the syndrome (CRS) as a major dose- limiting side effect. For of Cancer 2020;8:e000621. maximal tolerated dose of a CEAxCD3 bsAb in doi:10.1136/jitc-2020-000621 CRS prevention, steroids are recommended prior to bsAb 7 treatment, despite their well-kno wn lymphotoxic activity. a recent clinical study. The IL-6 receptor antibody tocilizumab is established for Meanwhile, the IL-6 receptor antibody tocili- ► Additional material is zumab is approved for treatment of severe published online only. To view treatment of CRS induced by CAR T cells, but was not please visit the journal online considered for CRS prevention in bsAb therapy.
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • NETTER, Jr., Robert, C. Et Al.; Dann, Dorf- (21) International Application
    ll ( (51) International Patent Classification: (74) Agent: NETTER, Jr., Robert, C. et al.; Dann, Dorf- C07K 16/28 (2006.01) man, Herrell and Skillman, 1601 Market Street, Suite 2400, Philadelphia, PA 19103-2307 (US). (21) International Application Number: PCT/US2020/030354 (81) Designated States (unless otherwise indicated, for every kind of national protection av ailable) . AE, AG, AL, AM, (22) International Filing Date: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, 29 April 2020 (29.04.2020) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (25) Filing Language: English DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, (26) Publication Language: English KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (30) Priority Data: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 62/840,465 30 April 2019 (30.04.2019) US OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, (71) Applicants: INSTITUTE FOR CANCER RESEARCH TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW. D/B/A THE RESEARCH INSTITUTE OF FOX CHASE CANCER CENTER [US/US]; 333 Cottman Av¬ (84) Designated States (unless otherwise indicated, for every enue, Philadelphia, PA 191 11-2497 (US). UNIVERSTIY kind of regional protection available) . ARIPO (BW, GH, OF KANSAS [US/US]; 245 Strong Hall, 1450 Jayhawk GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, Boulevard, Lawrence, KS 66045 (US).
    [Show full text]
  • Bi-Specific and Tri-Specific Antibodies- the Next Big Thing in Solid Tumor Therapeutics Karie Runcie1, Daniel R
    Runcie et al. Molecular Medicine (2018) 24:50 Molecular Medicine https://doi.org/10.1186/s10020-018-0051-4 REVIEW Open Access Bi-specific and tri-specific antibodies- the next big thing in solid tumor therapeutics Karie Runcie1, Daniel R. Budman1,2, Veena John1,2 and Nagashree Seetharamu1,2* Abstract Antibody-based therapy has revitalized the world of cancer therapeutics since rituximab was first approved for the treatment of Non-Hodgkin’s Lymphoma. Monoclonal antibodies against cancer antigens have been successful strategies for only a handful of cancer types due to many reasons including lack of antibody specificity and complex nature of tumor milieu which interfere with antibody efficacy. Polyspecific antibodies are promising class of anti-cancer agents which can be directed at multiple tumor antigens to eradicate tumor cells more precisely and effectively. They may overcome some of these limitations and have already changed treatment landscape for some malignancies such as B cell acute lymphoblastic leukemia. Pre-clinical studies and early phase clinical trials have demonstrated that this approach may be an effective strategy even for solid tumors. This review focuses on the development of bispecific and trispecific antibody therapy for the treatment of solid tumor malignancies and highlights the potential they hold for future therapies to come. Keywords: Bispecific antibody, Trispecific antibody, Immunotherapy, Solid tumor Background efficacy in various cancers, these agents are rarely effect- Cancer remains the second leading cause of death in the ive as monotherapies and have several limitations. Acti- United States, with lung cancer being the leading cause vation of alternate molecular pathways, acquired of cancer deaths, followed by breast cancer in women changes in the tumor milieu, and suboptimal engage- and prostate cancer in men (Siegel 2017).
    [Show full text]
  • (INN) for Biological and Biotechnological Substances
    WHO/EMP/RHT/TSN/2019.1 International Nonproprietary Names (INN) for biological and biotechnological substances (a review) 2019 WHO/EMP/RHT/TSN/2019.1 International Nonproprietary Names (INN) for biological and biotechnological substances (a review) 2019 International Nonproprietary Names (INN) Programme Technologies Standards and Norms (TSN) Regulation of Medicines and other Health Technologies (RHT) Essential Medicines and Health Products (EMP) International Nonproprietary Names (INN) for biological and biotechnological substances (a review) FORMER DOCUMENT NUMBER: INN Working Document 05.179 © World Health Organization 2019 All rights reserved. Publications of the World Health Organization are available on the WHO website (www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications –whether for sale or for non-commercial distribution– should be addressed to WHO Press through the WHO website (www.who.int/about/licensing/copyright_form/en/index.html). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned.
    [Show full text]
  • Discovery Strategies to Maximize the Clinical Potential of T-Cell Engaging Antibodies for the Treatment of Solid Tumors
    antibodies Review Discovery Strategies to Maximize the Clinical Potential of T-Cell Engaging Antibodies for the Treatment of Solid Tumors Vladimir Voynov 1,*, Paul J. Adam 2, Andrew E. Nixon 1 and Justin M. Scheer 1 1 Biotherapeutics Discovery, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA; [email protected] (A.E.N.); [email protected] (J.M.S.) 2 Cancer Immunology & Immune Modulation, Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer-Gasse 5-11, 1121 Vienna, Austria; [email protected] * Correspondence: [email protected] Received: 13 September 2020; Accepted: 11 November 2020; Published: 18 November 2020 Abstract: T-cell Engaging bispecific antibodies (TcEs) that can re-direct cytotoxic T-cells to kill cancer cells have been validated in clinical studies. To date, the clinical success with these agents has mainly been seen in hematologic tumor indications. However, an increasing number of TcEs are currently being developed to exploit the potent mode-of-action to treat solid tumor indications, which is more challenging in terms of tumor-cell accessibility and the complexity of the tumor microenvironment (TME). Of particular interest is the potential of TcEs as an immunotherapeutic approach for the treatment of non-immunogenic (often referred to as cold) tumors that do not respond to checkpoint inhibitors such as programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) antibodies. This has led to considerable discovery efforts for, firstly, the identification of tumor selective targeting approaches that can safely re-direct cytotoxic T-cells to cancer cells, and, secondly, bispecific antibodies and their derivatives with drug-like properties that promote a potent cytolytic synapse between T-cells and tumor cells, and in the most advanced TcEs, have IgG-like pharmacokinetics for dosing convenience.
    [Show full text]
  • IMPROVE Patient Outcomes Thursday, Dec
    IMPROVE Patient Outcomes Thursday, Dec. 10, 2020 • Louisville, Ky. Live Virtual Program #LearnACI The 2020–2021 ACI series is jointly provided by Postgraduate Institute for Medicine and the Society for Immunotherapy of Cancer in collaboration with the American Academy of Emergency Medicine, the Association of Community Cancer Centers and the Hematology/Oncology Pharmacy Association. SITC-0720-148 Thank You To Our Supporters The 2020–2021 Advances in Cancer ImmunotherapyTM series is generously supported in part by independent medical education grants from: DOUBLE-PLATINUM AstraZeneca Pharmaceuticals LP Merck & Co., Inc. PLATINUM Bristol Myers Squibb GOLD Amgen SILVER Exelixis, Inc. Table of Contents Letter from the President . 2 Program Details . 3 Program Planners and Faculty . 6 Program Schedule . 7 Disclosure Information . 8 Program Organizers . 11 Presentations Immunotherapy for the Treatment of Skin Cancers Jae Y. Jung, MD, PhD Norton Cancer Institute . 12 Immunotherapy for the Treatment of Lung Cancer Adam Lye, MD Norton Cancer Institute . 39 Immunotherapy for the Treatment of Hematologic Malignancies Joseph Maly, MD Norton Cancer Institute . 65 Immunotherapy for the Treatment of Genitourinary Malignancies Chandler H. Park, MD Norton Cancer Institute . 90 Immunotherapy for the Treatment of Head and Neck Cancers Aaron Spalding, MD, PhD Norton Cancer Institute . 106 Immunotherapy for the Treatment of Additional Solid Tumors: GI Mike Driscoll, MD Norton Cancer Institute . 121 Practical Barriers in Cancer Immunotherapy Treatment Lennea Coombs, MHS, PA-C Norton Cancer Institute . 136 Toxicity Management Laila Agrawal, MD Norton Cancer Institute . 154 What’s Next for Cancer Immunotherapy? Jaspreet S. Grewal, MD, PhD, MPH Norton Cancer Institute . 180 COVID-19 in Cancer Immunotherapy Joseph Flynn, MD, MPH Norton Cancer Institute .
    [Show full text]
  • Multifunctional Receptor-Targeting Antibodies for Cancer Therapy
    Review Multifunctional receptor-targeting antibodies for cancer therapy Yanni Zhu, Sung Hugh Choi, Khalid Shah During the past decade, monospecifi c antibodies targeting cell-surface receptors in diff erent tumour types have Lancet Oncol 2015; 16: e543–54 achieved substantial success and have been at the forefront of cancer treatment. However, redundant signalling and Molecular Neurotherapy and crosstalk between diff erent pathways within tumour cells and between tumour cells and their microenvironment can Imaging Laboratory, Stem Cell limit the effi cacy of receptor-targeted monospecifi c-based therapies. Advances in antibody engineering technologies Therapeutics and Imaging Program (Y Zhu PhD, have enabled strategies that simultaneously target multiple receptors to circumvent the limitations of conventional S H Choi PhD, K Shah PhD), monospecifi c therapies and achieve enhanced therapeutic effi cacy. In the past 5 years, a range of multifunctional, Department of Radiology receptor-targeting, antibody-based molecules have emerged, which allow targeting of multiple surface receptors on (Y Zhu, S H Choi, K Shah), and tumour cells and endothelial or immune cells in the tumour microenvironment. In this Review, we discuss the Department of Neurology (K Shah), Massachusetts rationales and strategies for the use of multifunctional receptor-targeting antibodies, their mechanisms of action, and General Hospital, Harvard the promises and challenges they hold as cancer therapeutics. This knowledge provides opportunities to improve Medical School, Boston, MA, current targeted therapy outcomes for patients with cancer. USA; and Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA (K Shah) Introduction penetrate to tumour tissues inaccessible to full-size Correspondence to: Antibody-based therapeutics have been one of the most antibodies.
    [Show full text]