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Research ArticleSpecial Section: From Insight to Modulation of CXCR4 and ACKR3 (CXCR7) Function – Minireview
Open Access

Antibodies Targeting Chemokine Receptors CXCR4 and ACKR3

Vladimir Bobkov, Marta Arimont, Aurélien Zarca, Timo W.M. De Groof, Bas van der Woning, Hans de Haard and Martine J. Smit
Molecular Pharmacology December 2019, 96 (6) 753-764; DOI: https://doi.org/10.1124/mol.119.116954
Vladimir Bobkov
Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (V.B., M.A., A.Z., T.W.M.D.G., M.J.S.); and argenx BVBA, Zwijnaarde, Belgium (V.B., B.W., H.H.)
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Marta Arimont
Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (V.B., M.A., A.Z., T.W.M.D.G., M.J.S.); and argenx BVBA, Zwijnaarde, Belgium (V.B., B.W., H.H.)
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Aurélien Zarca
Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (V.B., M.A., A.Z., T.W.M.D.G., M.J.S.); and argenx BVBA, Zwijnaarde, Belgium (V.B., B.W., H.H.)
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Timo W.M. De Groof
Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (V.B., M.A., A.Z., T.W.M.D.G., M.J.S.); and argenx BVBA, Zwijnaarde, Belgium (V.B., B.W., H.H.)
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Bas van der Woning
Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (V.B., M.A., A.Z., T.W.M.D.G., M.J.S.); and argenx BVBA, Zwijnaarde, Belgium (V.B., B.W., H.H.)
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Hans de Haard
Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (V.B., M.A., A.Z., T.W.M.D.G., M.J.S.); and argenx BVBA, Zwijnaarde, Belgium (V.B., B.W., H.H.)
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Martine J. Smit
Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (V.B., M.A., A.Z., T.W.M.D.G., M.J.S.); and argenx BVBA, Zwijnaarde, Belgium (V.B., B.W., H.H.)
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    Fig. 1.

    Overview of antibody formats. (A) Schematic representation of the structure of a conventional antibody (Conv. Ab), heavy chain–only antibody (HCAb), and immunoglobulin new antigen receptor (IgNAR). The antibodies consist of constant domains [constant heavy (CH) and constant light (CL)] and variable domains [variable heavy (VH), variable light (VL), variable heavy chain region of a heavy chain–only antibody (VHH), or variable fragment of immunoglobulin new antigen receptor (VNAR)], which make up the Fc region and Fab domains. (B) Overview of commonly used fragments derived from Conv. Abs, HCAbs, or IgNARs. Bispec. Nb, bispecific nanobody; Biv. Nb, bivalent nanobody; Nb, nanobody; Nb-Fc, nanobody-Fc fusion protein; scFv, single-chain variable fragment.

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    Fig. 2.

    Three-dimensional models of a conventional antibody (left), a nanobody-Fc fusion protein (middle), and a nanobody (right). These models were produced by homology modeling in the software modeler (version 9.15) (Webb and Sali, 2017) and are based on the crystal structure with Protein Data Bank identifier: 1HZH (Saphire et al., 2001) as a template. The sequence of the nanobody corresponds to the Nb VUN400 (Van Hout et al., 2018). CH, constant heavy; CL, constant light; Conv. Ab, conventional antibody; VH, variable heavy; VL, variable light; VHH, variable heavy chain region of a heavy chain–only antibody.

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    Fig. 3.

    Differences between the reactivity, Kd, or IC50 values of wild-type (WT) and mutant (WT value − mutant value/WT value) reported for 17 CXCR4 antibodies, nanobodies, and antibody-like scaffolds extracted from the literature (Brelot et al., 1999, 2000; Gerlach et al., 2001; Rosenkilde et al., 2004, 2007; Carnec et al., 2005; Jähnichen et al., 2010; Thiele et al., 2014; Griffiths et al., 2016; Peng et al., 2016a; de Wit et al., 2017; Van Hout et al., 2018). The effects are colored for easier interpretation as follows: blue for the less significant effect (reactivity difference 0–0.5, Kd/IC50 difference 0- to 3-fold units), yellow for an intermediate effect (reactivity difference 0.5–0.7, Kd/IC50 difference 3- to 8-fold units), and red for the most significant effects (reactivity difference 0.7–1, Kd/IC50 difference > 8-fold units).

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    Fig. 4.

    CXCR4 snake plot representations with the most relevant residues involved on the binding of each antibody and antibody-like scaffold (A) or nanobody (B), as indicated in Fig. 3. Snake plots are based on GPCRdb representations (Pándy-Szekeres et al., 2018).

Tables

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    TABLE 1

    Comparison of therapeutic antibodies and small-molecule compounds targeting GPCRs

    AntibodySmall Molecule
    General properties
      Mostly antagonistsAntagonists, agonists, and allosteric modulators
      Preference for extracellular epitopesBinding multiple pockets, including intracellular
      Administration mostly intravenous or subcutaneousOral administration possible
      Immunogenicity minimized by humanizationLow risk for immunogenicity
      Effector functionsNo effector functions
     Longer serum half-life, reduced dosing frequencyShorter serum half-life, variable dosing frequency
     Restricted blood-brain barrier penetrationGood blood-brain barrier penetration
    Development
     High target expression during immunization and selection neededDevelopment not dependent on target expression
     Higher costs of development and manufacturingLower costs of development and manufacturing
    GPCR targeting
     Possibility of targeting low-druggability GPCRsPoor tractability, failed to target a variety of GPCRs (e.g., class B2, F)
     Enhanced selectivity and specificityLower selectivity, often target family-conserved binding sites
     Less off-target effectsOff-target effects
    Applications
      Easy to label and functionalize, e.g., bispecifics, fragments, and conjugatesChallenging to label
    Clinical development
     Lower overall rate of attrition and higher transition rates at all stages of developmentLower approval success rates
    • View popup
    TABLE 2

    Overview of monoclonal antibodies, nanobodies, and antibody-based fragments and scaffolds directed at and modulating CXCR4 and ACKR3 function

    Antibody (Company)TargetFormatMechanism of ActionIndicationPhaseReference
    Ulocuplumab (Bristol-Myers Squibb)CXCR4hIgG4CXCR4 inhibition, apoptosis inductionAMLPhase 1/2 ongoing (NCT02305563)Kuhne et al. (2013), Kashyap et al. (2016)
    WMPhase 1/2 ongoing (NCT03225716)
    LY2624587 (Eli Lilly and Company)CXCR4hzIgG4CXCR4 inhibition, apoptosis inductionMetastatic cancerPhase 1 completed (NCT01139788)Peng et al. (2016b, 2017)
    PF-06747143 (Pfizer)CXCR4hzIgG1CXCR4 inhibition, apoptosis induction, ADCC, and CDCAMLPhase 1 terminated (NCT02954653)Kashyap et al. (2017), Liu et al. (2017), Zhang et al. (2017)
    hz515H7/F50067 (Pierre Fabre)CXCR4hzIgG1CXCR4 inhibition, ADCC, and CDCMMPhase 1Broussas et al. (2016), Fouquet et al. (2018)
    MEDI3185 (Medimmune)CXCR4hIgG1mutCXCR4 inhibition, apoptosis inductionHematologic malignanciesPreclinicalKamal et al. (2013), Peng et al. (2016a), Schwickart et al. (2016)
    IgGX-auristatinCXCR4IgG, ADCAuristatin-mediated cytotoxicityMetastatic cancerPreclinicalKularatne et al. (2014)
    238D2, 238D4 (Ablynx)CXCR4NbCXCR4 inhibition, anti-HIV activity, HSC mobilization—PreclinicalJähnichen et al. (2010)
    10A10CXCR4NbCXCR4 inhibitionWHIM syndromePreclinicalde Wit et al. (2017)
    VUN400-402CXCR4NbCXCR4 inhibition, anti-HIV activity—PreclinicalVan Hout et al. (2018)
    VUN400-402CXCR4Nb-FcCXCR4 inhibition, anti-HIV activity, ADCC, and CDC—PreclinicalBobkov et al. (2018b)
    AD-114 (AdAlta)CXCR4i-bodyCXCR4 inhibition, anti-HIV activityIPFPreclinicalGriffiths et al. (2016, 2018)
    bAb-AC1, bAb-AC4CXCR4Antibody scaffoldCXCR4 inhibition—PreclinicalLiu et al. (2014)
    NB1-3 (Ablynx)ACKR3NbACKR3 inhibitionHead and neck cancerPreclinicalMaussang et al. (2013)
    X7AbACKR3scFv-FcACKR3 inhibition, ADCC, CDC, and ADCPGBMPreclinicalSalazar et al. (2018)
    • ADC, antibody-drug conjugate; ADCP, antibody-dependent cellular phagocytosis; AML, acute myeloid leukemia; GBM, glioblastoma; hIgG, human IgG; HSC, hematopoietic stem cell; hzIgG, humanized IgG; IgG1mut, triple mutant lacking ADCC and CDC; IPF, idiopathic pulmonary fibrosis; Nb-Fc, nanobody fused with Fc domain from IgG1; scFv, single-chain variable fragment fused with Fc domain from IgG1; WHIM, warts, hypogammaglobulinemia, infections, and myelokathexis; WM, Waldenström’s macroglobulinemia.

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Molecular Pharmacology: 96 (6)
Molecular Pharmacology
Vol. 96, Issue 6
1 Dec 2019
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Research ArticleSpecial Section: From Insight to Modulation of CXCR4 and ACKR3 (CXCR7) Function – Minireview

Antibodies Targeting CXCR4 and ACKR3

Vladimir Bobkov, Marta Arimont, Aurélien Zarca, Timo W.M. De Groof, Bas van der Woning, Hans de Haard and Martine J. Smit
Molecular Pharmacology December 1, 2019, 96 (6) 753-764; DOI: https://doi.org/10.1124/mol.119.116954

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Research ArticleSpecial Section: From Insight to Modulation of CXCR4 and ACKR3 (CXCR7) Function – Minireview

Antibodies Targeting CXCR4 and ACKR3

Vladimir Bobkov, Marta Arimont, Aurélien Zarca, Timo W.M. De Groof, Bas van der Woning, Hans de Haard and Martine J. Smit
Molecular Pharmacology December 1, 2019, 96 (6) 753-764; DOI: https://doi.org/10.1124/mol.119.116954
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  • Article
    • Abstract
    • Introduction
    • Targeting CXCR4 and ACKR3 with Antibodies
    • Single-Domain Antibodies as Therapeutics and Tools in GPCR Research
    • Structural Analysis of Antibodies/Nanobodies Binding to CXCR4
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  • ACKR3 Expression and Function in the Immune System
  • ACKR3 in Breast, Lung, and Brain Cancer
  • Modulators of CXCR4 and CXCR7/ACKR3 Function
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