Next Generation Antibody Drug Conjugates (ADCs) and Immunotoxins PDF
Preview Next Generation Antibody Drug Conjugates (ADCs) and Immunotoxins
Milestones in Drug Therapy Series Editors: Michael J. Parnham · Jacques Bruinvels Ulf Grawunder Stefan Barth Editors Next Generation Antibody Drug Conjugates (ADCs) and Immunotoxins Milestones in Drug Therapy Series editors Michael J. Parnham, Fraunhofer IME & Goethe University Frankfurt, Germany Jacques Bruinvels, Bilthoven, The Netherlands Advisory Board J.C. Buckingham, Imperial College School of Medicine, London, UK R.J. Flower, The William Harvey Research Institute, London, UK A.G. Herman, Universiteit Antwerpen, Antwerp, Belgium P. Skolnick, National Institute on Drug Abuse, Bethesda, MD, USA Moreinformationaboutthisseriesathttp://www.springer.com/series/4991 Ulf Grawunder (cid:129) Stefan Barth Editors Next Generation Antibody Drug Conjugates (ADCs) and Immunotoxins Editors UlfGrawunder StefanBarth NBE-TherapeuticsLtd. FacultyofHealthSciences Basel,Switzerland UniversityofCapeTown CapeTown,SouthAfrica ISSN2296-6056 ISSN2296-6064 (electronic) MilestonesinDrugTherapy ISBN978-3-319-46875-4 ISBN978-3-319-46877-8 (eBook) DOI10.1007/978-3-319-46877-8 LibraryofCongressControlNumber:2017937530 ©SpringerInternationalPublishingAG2017 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartof the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilarmethodologynowknownorhereafterdeveloped. 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Printedonacid-freepaper ThisSpringerimprintispublishedbySpringerNature TheregisteredcompanyisSpringerInternationalPublishingAG Theregisteredcompanyaddressis:Gewerbestrasse11,6330Cham,Switzerland Preface Thespecifictargetingoftoxicsubstancestodiseasetargetsisahistoricconceptthat was already developed by Paul Ehrlich more than 100 years ago, for which he coined the term “magic bullet” (Zauberkugel). A “magic bullet” should only destroy the target expressing disease entity, but leave target-negative cells unaf- fected. While Paul Ehrlich developed the “magic bullet” concept primarily in the areaofinfectiousdisease,thisprinciplecanalsoperfectlybeappliedtothefieldof oncology. During the past two decades therapeutic antibodies have led to a revolution of targeted cancer therapy, with more than 30 therapeutic antibodies and antibody fragments, including major blockbusters like trastuzumab (Herceptin®) or rituximab(Mabthera®),beingFDA and EMA approved.In the field ofoncology, the“magicbullet”conceptofPaulEhrlichispursuedbyattachingcellulartoxinsto cancer cell-specific antibodies or antibody fragments, in order to specifically deliver the toxic payload to the site of the tumor. In the broadest definition, these drugsbelongtotheclassofimmuno-conjugates,inwhichanactivepharmaceutical ingredient (API), with a desired pharmacological effect, is attached to a targeting moietybasedonanimmune-targetingmolecule,e.g.,anantibody,asolublerecep- tor, or a ligand for a specific disease target. Immuno-conjugates comprised of an antibody or antibody binding domain coupled to a potent cellular toxin can be grouped into two classes: antibody drug conjugates (ADCs) and immunotoxins (ITs),andbothtypesofmoleculesaresubjectsofintenseresearch,bothinpreclin- icalandclinicalresearch. In ADCs, the toxic payload is a small molecular weight compound which is coupledorconjugatedto(a)reactivesite(s)oftheantibodyorantibodyfragmentby meansofalinker,eitherbymeansofachemical,orviaanenzymaticreaction.In contrast,immunotoxinsarecomprisedofanantibodyoranantibodyfragment(e.g., F orscF fragment)coupledtoaproteintoxin. ab v Whiletheconceptoftargetingatoxintoacancercellbymeansofacancercell- specificantibodyiscompelling,researchduringthelasttwodecadeshasshownthat the practical implementation of Paul Ehrlich’s “magic bullet” principle in ADCs v vi Preface and ITs is anything but trivial. This is due to the fact that both in ADCs and immunotoxins a multitude of functionalities need to be combined in a single, largebiologicaldrugmolecule—ifonlyasinglefunctionalaspectofthesecomplex molecules is not optimal, this will become the limiting factor in determining the therapeuticindexofthedrug. The Complexity of ADCs and ITs Finding a Suitable Target The task of developing an effective ADC or IT with promisingtherapeuticindexalreadystartswiththeselectionofthecancertarget.If thetargetisnotselectivelyexpressedontumorcells,eventhemostperfectADCor ITdesignwillnotbeabletorescuethetherapeuticindexofsuchaconjugate.This represents not only the first but also one of the most important challenges in immuno-conjugate research. In fact, it is believed that the “target space” address- able with highly potent ADCs and ITs may be limited to just a few dozen targets that based on tumor selective expression qualify for ADC or IT intervention strategies. Even for FDA-approved ADCs this remains a challenge. For instance, ® the HER2 antigen recognized by FDA-approved ADC Kadcyla is also widely expressed at low levels on healthy cells or tissues and very unfavorably also on cardiomyocytes. HER2 expression on healthy cells represents an even higher risk ® for the ADC Kadcyla than for the unconjugated FDA-approved therapeutic ® antibody Herceptin (trastuzumab), for which a cardiotoxic effect is already documented. Therefore, the therapeutic index of an ADC or IT, in first instance, isverysignificantlyinfluencedbytheratiooftargetexpressionontumorcellsver- sus target expression on healthy cells. This ratio should ideally be as high as possible.ThepenandBartharesummarizingtheuseofCD64(Fcgammareceptor I) exclusively expressed on monocytes and macrophages for the development of recombinant immunotoxins. By selective destruction of M1-type macrophages, these agents might allow treatment of monocyte-derived leukemia as well as differentchronicinflammatorydiseases. TargetInternalization OnceatargetforADCandITstrategieshasbeenidenti- fied, the target needs to be able to internalize into the cancer cell, to ensure intracellulartraffickingintoendosomalandlysosomalcompartmentsallowing the toxophore to be released inside the tumor cell. Not every target has a sufficient internalization rate allowingtransportadequateamounts ofthetoxophore intothe cancer cell to effect its destruction. Here is a clear advantage of immunotoxins versusantibodydrugconjugates.Theproteintoxinsfusedtoantibodyfragmentsin immunotoxins(e.g.,bacterialdiphtheriatoxinorpseudomonasexotoxin)actcata- lyticallyontheirintracellularsubstrate,andtheyareofteneffectiveforcellkilling, evenifonlyaverysmallnumberofmoleculesareinternalizedandtranslocatedto the cytosol. Therefore, ITs are better suited to address cancer targets that are expressedatlowlevelsand/orwithapotentiallylowinternalizationrate. Preface vii However,insomecases,targetinternalizationisafunctionoftheepitopethatis bound by the targeting antibody or antibody fragment. There are many examples showing that antibodies binding different epitopes on a selected target can have a hugeimpactontheinternalizationrateforanADCorIT. Alternatively, and this has mostly been postulated in the ADC space, it is possible to design linkers in such a way that they are cleaved in the tumor microenvironment, without the need for target internalization, thereby effecting killing of the tumor cells and also neighboring supportive tumor stromal and vasculartissuesthatsupporttumorgrowth.However,thebalancebetweeneffecting efficient releaseofatoxic payload atthesite ofthe tumor,butnotprematurelyin circulationisquiteachallengingtask. PropertiesoftheTargetingMoiety Inadditiontoidentifyingtherighttarget,in terms of tumor selective expression and internalization capabilities, the targeting moiety itself needs to exhibit, what is known in the field as, favorable “developability” properties. This essentially boils down to assuring favorable physiologic properties of the ADC or IT upon systemic application of the drugs. Ingeneralterms,thedrugsshouldhavelowimmunogenicityandappropriateserum half-lifeorpharmacokineticpropertiesinvivo.Manyyearsofresearchanddevel- opmentoftherapeuticantibodieshaveledtoawealthofknowledgethatnowadays stronglyinfluencethedesign,theengineering,andtheselectionofafinalantibody candidate as a basis for antibody-based targeted therapy. Antibodies selected for ADC and IT strategies will at least be humanized or developed outright as fully human antibodies. However, selected binders will probably additionally be subjected to the removal of additional T-cell epitopes to minimize their immuno- genic potential in humans. At the same time, other sequence liabilities will be addressedwiththeaimtoincreasethermalandpHstability,toreducepropensityfor aggregation,especiallyathighconcentration.Eventually,alltheoptimizationofthe biophysical and physiological parameters of the antibody moiety needs to be balanced with the expression levels of the antibody in fermentation, so that it can alsobemanufactured atcommercialscale withacceptablecostofgoods(COGS). In other words, even if “Finding the right target” and “Target internalization” as describedaboveareproperlyaddressed,unfavorablepropertiesofanantibodycan bedetrimentalforthedevelopmentofaneffectiveADCorIT. Selection of Toxin Payload In addition to the selection of the right target and antibodyforanADCorIT,thechoiceofthetoxophoreastheactivepharmaceutical ingredient (API) is as important. While in the field of recombinant ITs only a limitednumberofbacterialandplanttoxinshavebeenemployed(e.g.,pseudomo- nas exotoxin, diphtheria toxin, gelonin), the choice of toxophores for ADCs is significantly larger and more complex, because any high-potency API chemical structurecanpotentiallybecoupledtoanADC.However,forrecombinantITs,itis not only the choice of protein toxin, but also the variant thereof, which can extensively be engineered, in order to optimize its potency and to reduce its risk of immunogenicity. The chapter by Kreitmann et al. from the laboratory of Ira Pastan at NIH highlights advances in the development of recombinant ITs viii Preface demonstratingtheactivityofBL22anditsderivativemoxetumomabpasudotoxfor thetreatmentofCD22-relatedB-celldisorders.InthefieldofADCs,themajorityof ADCs in clinical evaluation carry tubulin-inhibiting payloads of the maytansin or dolastatin/auristatin class, derived from the bark of an African shrub Maytenus ovatus, or a sea slug Dolabella auricularia, respectively. These toxins interfere withtubulinpolymerizationandthereforewiththere-organizationoftheintracel- lular cytoskeleton, which is required for cell proliferation and cell motility (i.e., cancer cell invasiveness). Therefore, these drugs target primarily rapidly prolifer- ating tumor cells. Alternatively, ADCs may comprise DNA damaging agents that can also lead to destruction of non-proliferating cells, by interfering with proper transcriptionofgenes.ThefirstADCthathadbeenFDAapprovedforthetreatment of CD33-positive acute myeloid leukemia (AML), Mylotarg® (gemtuzumab ozogamicin), contained the DNA damaging toxin calicheamicin as a payload. The chapter by H.P. Gerber and P. Supra provides detailed background about the calicheamicintoxinplatformforADCsanddescribestheuseofthispayloadforthe developmentofanti-CD22ADCsthataresubjecttoclinicaldevelopmentactivities at Pfizer. In addition to the calicheamycin DNA damaging toxin platform, most recentlyso-calledpyrrolo-benzo-diazepines(PBDs)haveenteredintothearenaof ADCs.ThePBDtoxinplatformisnowadaysemployedbymanyADCresearchers fordevelopingnext-generationADCs,both academicallyandcommercially.John Hartley from UCL, one of the key opinion leaders in the PBD toxin field, has contributedachapterdescribingthe currentstateofthe artinthisfield.However, other toxin platforms, either DNA damaging (duocarmycins, anthracyclines) or targetingothercellularpathways,e.g.,alpha-amanitinbindingtoRNApolymerase IIandIII,arealsobeingexploredinnewergenerationADCs. LinkerFunctionality AnotherhighlycriticalcomponentofanADCisthelinker structure that covalently attaches the toxophore to the targeting moiety. On one hand this linker needs to ensure that premature release of the toxin (e.g. in circu- lation)isavoided.Ontheotherhand,thelinkershouldefficientlyreleasethetoxin uponbindingtothecancer cellsand/or uponinternalizationoftheADC/ITinside the cancer cell. First-generation ADCs, including the two FDA-approved ADC ® products Kadcyla (trastuzumab-emtansine) for the treatment of HER2-positive ® breast and ovarian cancer and Adcetris for CD30-positive Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL), use chemical linkers that are classified as “non-cleavable” or “cleavable,” respectively, which couple the toxin randomly to either lysine or cysteine residues. The functional aspects of these traditional chemical linker approaches, but more importantly the state of the art of newer approaches for chemical conjugation, with respect to stability and site specificity,areoutlinedinthecontributionsbyPabstandcolleaguesfromAbzena and Nanna and colleagues from the group of Christoph Rader from The Scripps ResearchInstitute(TSRI). Recombinant immunotoxins comprise the toxins as fusions to the antibody or antibodyfragment.Thelinkbetweenthetwofusionpartnersthereforeisanormal peptidebondoraspacerpeptide.Inthesedrugs,itneedstobeassuredthattheway Preface ix of fusion either does not interfere with the catalytic function of the protein toxin and/orthataspecificrelease/translocationiseffectedbyintracellularproteases. Similarly, next-generation ADCs generated by site-specific conjugation using enzymatic approaches, as outlined in the chapter by Beerli and Grawunder, are characterized by the formation of stable peptide or amide bonds that require the action of specific or non-specific proteases, in order to optimally release the toxophore in cancer cells. Clearly, without an optimal linker technology, which confers the proper spatial and temporal release of the toxin from an ADC or immunotoxin,afavorabletherapeuticindexcannotbeachieved. Conclusion The field of ADC and immunotoxin development has entered into a new era. Novel “next-generation” ADCs and ITs employing different linker tech- nologies, both chemical and enzymatic, different small molecular toxins, and engineeredversionofproteintoxins,areincreasinglyenteringintopreclinicaland clinical evaluation. All chapters in this book on “next-generation” ADCs and immunotoxins contributed by eminent researchers and key opinion leader in the fieldofADCandITdevelopmentprovideanoutlookonexcitingnoveltherapeutic principles and formats of immuno-conjugates that will hopefully soon be able to curehumandiseaseinasaferandmoreeffectivemanner. Basel,Switzerland UlfGrawunder CapeTown,SouthAfrica StefanBarth
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