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4. C1q binding to surface-bound IgG is stabilized by C1r₂s₂ proteases

Author

Zwarthoff, Seline A., Widmer, Kevin, Kuipers, Annemarie, Strasser, Jürgen, Ruyken, Maartje, Aerts, Piet C., de Haas, Carla J. C., Ugurlar, Deniz, den Boer, Maurits A., Vidarsson, Gestur, van Strijp, Jos A. G., Gros, Piet, Parren, Paul W. H. I., van Kessel, Kok P. M., Preiner, Johannes, Beurskens, Frank J., Schuurman, Janine, Ricklin, Daniel, and Rooijakkers, Suzan H. M.

Published
2021

6. Targeted complement inhibition using bispecific antibodies that bind local antigens and endogenous complement regulators

Author

Wang, Haiyu, van de Bovenkamp, Fleur S., Dijkstra, Douwe J., Abendstein, Leoni, Borggreven, Nicole V., Pool, Jos, Zuijderduijn, Rob, Gstoettner, Christoph, Gelderman, Kyra A., Damelang, Timon, Vidarsson, Gestur, Blom, Anna M., Dominguez-Vega, Elena, Parren, Paul W. H. I., Sharp, Thomas H., Trouw, Leendert A., Wang, Haiyu, van de Bovenkamp, Fleur S., Dijkstra, Douwe J., Abendstein, Leoni, Borggreven, Nicole V., Pool, Jos, Zuijderduijn, Rob, Gstoettner, Christoph, Gelderman, Kyra A., Damelang, Timon, Vidarsson, Gestur, Blom, Anna M., Dominguez-Vega, Elena, Parren, Paul W. H. I., Sharp, Thomas H., and Trouw, Leendert A.

Abstract

Complement activation protects against infection but also contributes to pathological mechanisms in a range of clinical conditions such as autoimmune diseases and transplant rejection. Complement-inhibitory drugs, either approved or in development, usually act systemically, thereby increasing the risk for infections. We therefore envisioned a novel class of bispecific antibodies (bsAbs) which are capable of site-directed complement inhibition by bringing endogenous complement regulators in the vicinity of defined cell surface antigens. Here, we analyzed a comprehensive set of obligate bsAbs designed to crosslink a specific target with either complement regulator factor H (FH) or C4b-binding protein (C4BP). The bsAbs were assessed for their capacity to inhibit complement activation and cell lysis in an antigen-targeted manner. We observed that the bsAbs inhibited classical, lectin, and alternative pathway complement activation in which sufficient endogenous serum FH and C4BP could be recruited to achieve local inhibition. Importantly, the bsAbs effectively protected antigen-positive liposomes, erythrocytes, and human leukocytes from complement-mediated lysis. In conclusion, localized complement inhibition by bsAbs capable of recruiting endogenous human complement regulators (such as FH or C4BP) to cell surfaces potentially provides a novel therapeutic approach for the targeted treatment of complement-mediated diseases.

Published
2024

9. Antibody-mediated delivery of viral epitopes to redirect EBV-specific CD8+ T-cell immunity towards cancer cells

Author

van der Wulp, Willemijn, primary, Remst, Dennis F. G., additional, Kester, Michel G. D., additional, Hagedoorn, Renate S., additional, Parren, Paul W. H. I., additional, van Kasteren, Sander I., additional, Schuurman, Janine, additional, Hoeben, Rob C., additional, Ressing, Maaike E., additional, Bleijlevens, Boris, additional, and Heemskerk, Mirjam H. M., additional

Published
2023
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10. DuoHexaBody-CD37®, a novel biparatopic CD37 antibody with enhanced Fc-mediated hexamerization as a potential therapy for B-cell malignancies

Author

Oostindie, Simone C., van der Horst, Hilma J., Kil, Laurens P., Strumane, Kristin, Overdijk, Marije B., van den Brink, Edward N., van den Brakel, Jeroen H. N., Rademaker, Hendrik J., van Kessel, Berris, van den Noort, Juliette, Chamuleau, Martine E. D., Mutis, Tuna, Lindorfer, Margaret A., Taylor, Ronald P., Schuurman, Janine, Parren, Paul W. H. I., Beurskens, Frank J., and Breij, Esther C. W.

Published
2020
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11. Targeted complement inhibition using bispecific antibodies that bind local antigens and endogenous complement regulators.

Author

Haiyu Wang, van de Bovenkamp, Fleur S., Dijkstra, Douwe J., Abendstein, Leoni, Borggreven, Nicole V., Pool, Jos, Zuijderduijn, Rob, Gstöttner, Christoph, Gelderman, Kyra A., Damelang, Timon, Vidarsson, Gestur, Blom, Anna M., Domínguez-Vega, Elena, Parren, Paul W. H. I., Sharp, Thomas H., and Trouw, Leendert A.

Subjects
COMPLEMENT inhibition, BISPECIFIC antibodies, ECULIZUMAB, COMPLEMENT factor H, CELL surface antigens, COMPLEMENT activation
Abstract

Complement activation protects against infection but also contributes to pathological mechanisms in a range of clinical conditions such as autoimmune diseases and transplant rejection. Complement-inhibitory drugs, either approved or in development, usually act systemically, thereby increasing the risk for infections. We therefore envisioned a novel class of bispecific antibodies (bsAbs) which are capable of site-directed complement inhibition by bringing endogenous complement regulators in the vicinity of defined cell surface antigens. Here, we analyzed a comprehensive set of obligate bsAbs designed to crosslink a specific target with either complement regulator factor H (FH) or C4b-binding protein (C4BP). The bsAbs were assessed for their capacity to inhibit complement activation and cell lysis in an antigen-targeted manner. We observed that the bsAbs inhibited classical, lectin, and alternative pathway complement activation in which sufficient endogenous serum FH and C4BP could be recruited to achieve local inhibition. Importantly, the bsAbs effectively protected antigen-positive liposomes, erythrocytes, and human leukocytes from complement-mediated lysis. In conclusion, localized complement inhibition by bsAbs capable of recruiting endogenous human complement regulators (such as FH or C4BP) to cell surfaces potentially provides a novel therapeutic approach for the targeted treatment of complement-mediated diseases. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Human anti-C1q autoantibodies bind specifically to solid-phase C1q and enhance phagocytosis but not complement activation

Author

MMB Research line 1, Infection & Immunity, Dijkstra, Douwe J, van de Bovenkamp, Fleur S, Abendstein, Leoni, Zuijderduijn, Rob, Pool, Jos, Kramer, Cynthia S M, Slot, Linda M, Drijfhout, Jan W, de Vor, Lisanne, Gelderman, Kyra A, Rooijakkers, Suzan H M, Zaldumbide, Arnaud, Vidarsson, Gestur, Sharp, Thomas H, Parren, Paul W H I, Trouw, Leendert A, MMB Research line 1, Infection & Immunity, Dijkstra, Douwe J, van de Bovenkamp, Fleur S, Abendstein, Leoni, Zuijderduijn, Rob, Pool, Jos, Kramer, Cynthia S M, Slot, Linda M, Drijfhout, Jan W, de Vor, Lisanne, Gelderman, Kyra A, Rooijakkers, Suzan H M, Zaldumbide, Arnaud, Vidarsson, Gestur, Sharp, Thomas H, Parren, Paul W H I, and Trouw, Leendert A

Published
2023

14. Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors

Author

Boshuizen, Julia, Koopman, Louise A, Krijgsman, Oscar, Shahrabi, Aida, van den Heuvel, Elke Gresnigt-, Ligtenberg, Maarten A, Vredevoogd, David W, Kemper, Kristel, Kuilman, Thomas, Song, Ji-Ying, Pencheva, Nora, Mortensen, Jens Thing, Foppen, Marnix Geukes, Rozeman, Elisa A, Blank, Christian U, Janmaat, Maarten L, Satijn, David, Breij, Esther C W, Peeper, Daniel S, and Parren, Paul W H I

Subjects
Drug therapy, Complications and side effects, Genetic aspects, Research, Dosage and administration, Biopharmaceuticals -- Health aspects -- Dosage and administration -- Complications and side effects, Antibodies -- Health aspects -- Dosage and administration -- Complications and side effects, Melanoma -- Health aspects -- Genetic aspects -- Drug therapy -- Research
Abstract

Author(s): Julia Boshuizen [1]; Louise A Koopman [2]; Oscar Krijgsman [1]; Aida Shahrabi [1]; Elke Gresnigt- van den Heuvel [2]; Maarten A Ligtenberg [1]; David W Vredevoogd [1]; Kristel Kemper [...], Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer lethality. Heterogeneous tumors show partial therapy responses, allowing for the emergence of drug-resistant clones that often express high levels of the receptor tyrosine kinase AXL. In melanoma, AXL-high cells are resistant to MAPK pathway inhibitors, whereas AXL-low cells are sensitive to these inhibitors, rationalizing a differential therapeutic approach. We developed an antibody-drug conjugate, AXL-107-MMAE, comprising a human AXL antibody linked to the microtubule-disrupting agent monomethyl auristatin E. We found that AXL-107-MMAE, as a single agent, displayed potent in vivo anti-tumor activity in patient-derived xenografts, including melanoma, lung, pancreas and cervical cancer. By eliminating distinct populations in heterogeneous melanoma cell pools, AXL-107-MMAE and MAPK pathway inhibitors cooperatively inhibited tumor growth. Furthermore, by inducing AXL transcription, BRAF/MEK inhibitors potentiated the efficacy of AXL-107-MMAE. These findings provide proof of concept for the premise that rationalized combinatorial targeting of distinct populations in heterogeneous tumors may improve therapeutic effect, and merit clinical validation of AXL-107-MMAE in both treatment-naive and drug-resistant cancers in mono- or combination therapy.

Published
2018
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15. Human anti-C1q autoantibodies bind specifically to solid-phase C1q and enhance phagocytosis but not complement activation.

Author

Dijkstra, Douwe J., van de Bovenkamp, Fleur S., Abendstein, Leoni, Zuijderduijn, Rob, Pool, Jos, Kramer, Cynthia S. M., Slot, Linda M., Drijfhout, Jan W., de Vor, Lisanne, Gelderman, Kyra A., Rooijakkers, Suzan H. M., Zaldumbide, Arnaud, Vidarsson, Gestur, Sharp, Thomas H., Parren, Paul W. H. I., and Trouw, Leendert A.

Subjects
PHAGOCYTOSIS, COMPLEMENT activation, AUTOANTIBODIES, IMMUNE response, IMMUNE complexes
Abstract

Autoantibodies directed against complement component C1q are commonly associated with autoimmune diseases, especially systemic lupus erythematosus. Importantly, these anti-C1q autoantibodies are specific for ligand-bound, solid-phase C1q and do not bind to fluid-phase C1q. In patients with anti-C1q, C1q levels are in the normal range, and the autoantibodies are thus not depleting. To study these human anti-C1q autoantibodies at the molecular level, we isolated C1q-reactive B cells and recombinantly produced nine monoclonal antibodies (mAbs) from four different healthy individuals. The isolated mAbs were of the IgG isotype, contained extensively mutated variable domains, and showed high affinity to the collagen-like region of C1q. The anti-C1q mAbs exclusively bound solid-phase C1q in complex with its natural ligands, including immobilized or antigen-bound IgG, IgM or CRP, and necrotic cells. Competition experiments reveal that at least 2 epitopes, also targeted by anti-C1q antibodies in sera from SLE patients, are recognized. Electron microscopy with hexameric IgG-C1q immune complexes demonstrated that multiple mAbs can interact with a single C1q molecule and identified the region of C1q targeted by these mAbs. The opsonization of immune complexes with anti-C1q greatly enhanced Fc-receptor-mediated phagocytosis but did not increase complement activation. We conclude that human anti-C1q autoantibodies specifically bind neo-epitopes on solid-phase C1q, which results in an increase in Fc-receptor-mediated effector functions that may potentially contribute to autoimmune disease immunopathology. [ABSTRACT FROM AUTHOR]

Published
2023
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16. Comparison of methods generating antibody-epitope conjugates for targeting cancer with virus-specific T cells

Author

van der Wulp, Willemijn, primary, Gram, Anna M., additional, Bleijlevens, Boris, additional, Hagedoorn, Renate S., additional, Araman, Can, additional, Kim, Robbert Q., additional, Drijfhout, Jan Wouter, additional, Parren, Paul W. H. I., additional, Hibbert, Richard G., additional, Hoeben, Rob C., additional, van Kasteren, Sander I., additional, Schuurman, Janine, additional, Ressing, Maaike E., additional, and Heemskerk, Mirjam H. M., additional

Published
2023
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17. Complement Is Activated by IgG Hexamers Assembled at the Cell Surface

Author

Diebolder, Christoph A., Beurskens, Frank J., de Jong, Rob N., Koning, Roman I., Strumane, Kristin, Lindorfer, Margaret A., Voorhorst, Marleen, Ugurlar, Deniz, Rosati, Sara, Heck, Albert J. R., van de Winkel, Jan G. J., Wilson, Ian A., Koster, Abraham J., Taylor, Ronald P., Saphire, Erica Ollmann, Burton, Dennis R., Schuurman, Janine, Gros, Piet, and Parren, Paul W. H. I.

Published
2014

18. Antibody-mediated delivery of viral epitopes to redirect EBV-specific CD8+T-cell immunity towards cancer cells

Author

van der Wulp, Willemijn, Remst, Dennis F. G., Kester, Michel G. D., Hagedoorn, Renate S., Parren, Paul W. H. I., van Kasteren, Sander I., Schuurman, Janine, Hoeben, Rob C., Ressing, Maaike E., Bleijlevens, Boris, and Heemskerk, Mirjam H. M.

Abstract

Antibody-mediated delivery of immunogenic epitopes to redirect virus-specific CD8+T-cells towards cancer cells is an emerging and promising new therapeutic strategy. These so-called antibody-epitope conjugates (AECs) rely on the proteolytic release of the epitopes close to the tumor surface for presentation by HLA class I molecules to eventually redirect and activate virus-specific CD8+T-cells towards tumor cells. We fused the immunogenic EBV-BRLF1 epitope preceded by a protease cleavage site to the C-terminus of the heavy and/or light chains of cetuximab and trastuzumab. We evaluated these AECs and found that, even though all AECs were able to redirect the EBV-specific T-cells, AECs with an epitope fused to the C-terminus of the heavy chain resulted in higher levels of T-cell activation compared to AECs with the same epitope fused to the light chain of an antibody. We observed that all AECs were depending on the presence of the antibody target, that the level of T-cell activation correlated with expression levels of the antibody target, and that our AECs could efficiently deliver the BRLF1 epitope to cancer cell lines from different origins (breast, ovarian, lung, and cervical cancer and a multiple myeloma). Moreover, in vivo, the AECs efficiently reduced tumor burden and increased the overall survival, which was prolonged even further in combination with immune checkpoint blockade. We demonstrate the potential of these genetically fused AECs to redirect the potent EBV-specific T-cells towards cancer in vitro and in vivo.

Published
2024
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19. Lava-051, a Novel Bispecific Gamma-Delta T-Cell Engager (Gammabody), in Relapsed/Refractory MM and CLL: Pharmacodynamic and Early Clinical Data

Author

Kater, Arnon P., primary, Van De Donk, Niels W.C.J., additional, Rodríguez-Otero, Paula, additional, Mateos, María Victoria, additional, Bosch, Francesc, additional, Tucci, Alessandra, additional, Ghia, Paolo, additional, Adang, Anton E.P., additional, Parren, Paul W. H.I., additional, Tuinhof, Ilse, additional, Umarale, Sanjana, additional, Winograd, Benjamin, additional, Van Der Vliet, Hans J., additional, and Broijl, Annemiek, additional

Published
2022
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21. Efficient generation of stable bispecific lgG1 by controlled Fab-arm exchange

Author

Labrijn, Aran F., Meesters, Joyce I., de Goeij, Bart E. C. G., van den Bremer, Ewald T. J., Neijssen, Joost, van Kampen, Muriel D., Strumane, Kristin, Verploegen, Sandra, Kundu, Amitava, Gramer, Michael J., van Berkel, Patrick H. C., van de Winkel, Jan G. J., Schuurman, Janine, and Parren, Paul W. H. I.

Published
2013

27. Biophysical characterization and stability of modified IgG1 antibodies with different hexamerization propensities

Author

van Kampen, Muriel D, Kuipers-De Wilt, Leonie H A M, van Egmond, Mariëlle L, Reinders-Blankert, Petra, van den Bremer, Ewald T J, Wang, Guanbo, Heck, Albert J R, Parren, Paul W H I, Beurskens, Frank J, Schuurman, Janine, de Jong, Rob N, van Kampen, Muriel D, Kuipers-De Wilt, Leonie H A M, van Egmond, Mariëlle L, Reinders-Blankert, Petra, van den Bremer, Ewald T J, Wang, Guanbo, Heck, Albert J R, Parren, Paul W H I, Beurskens, Frank J, Schuurman, Janine, and de Jong, Rob N

Abstract

The hexamerization of natural, human IgG antibodies after cell surface antigen binding can induce activation of the classical complement pathway. Mutations stimulating Fc domain-mediated hexamerization can potentiate complement activation and induce the clustering of cell surface receptors, a finding that was applied to different clinically investigated antibody therapeutics. Here, we biophysically characterized how increased self-association of IgG1 antibody variants with different hexamerization propensity may impact their developability, rather than functional properties. Self-Interaction Chromatography, Dynamic Light Scattering and PEG-induced precipitation showed that IgG variant self-association at neutral pH increased in the order wild type (WT) < E430G < E345K < E345R < E430G-E345R-S440Y, consistent with functional activity. Self-association was strongly pH-dependent, and single point mutants were fully monomeric at pH 5. Differential Scanning Calorimetry and Fluorimetry showed that mutation E430G decreased conformational stability. Interestingly, heat-induced unfolding facilitated by mutation E430G was reversible at 60°C, while a solvent-exposed hydrophobic mutation caused irreversible aggregation. Remarkably, neither increased dynamic self-association propensity at neutral pH nor decreased conformational stability substantially affected the stability of concentrated variants E430G or E345K during storage for two years at 2-8°C. We discuss how these findings may inform the design and development of IgG-based therapeutics.

Published
2022

28. Biophysical characterization and stability of modified IgG1 antibodies with different hexamerization propensities

Author

Sub Biomol.Mass Spectrometry & Proteom., Afd Biomol.Mass Spect. and Proteomics, Dep Scheikunde, Biomolecular Mass Spectrometry and Proteomics, van Kampen, Muriel D, Kuipers-De Wilt, Leonie H A M, van Egmond, Mariëlle L, Reinders-Blankert, Petra, van den Bremer, Ewald T J, Wang, Guanbo, Heck, Albert J R, Parren, Paul W H I, Beurskens, Frank J, Schuurman, Janine, de Jong, Rob N, Sub Biomol.Mass Spectrometry & Proteom., Afd Biomol.Mass Spect. and Proteomics, Dep Scheikunde, Biomolecular Mass Spectrometry and Proteomics, van Kampen, Muriel D, Kuipers-De Wilt, Leonie H A M, van Egmond, Mariëlle L, Reinders-Blankert, Petra, van den Bremer, Ewald T J, Wang, Guanbo, Heck, Albert J R, Parren, Paul W H I, Beurskens, Frank J, Schuurman, Janine, and de Jong, Rob N

Published
2022

33. Epidermal Growth Factor Receptor as Target for Perioperative Elimination of Circulating Colorectal Cancer Cells

Author

Gruijs, Mandy, primary, Braster, Rens, additional, Overdijk, Marije B., additional, Hellingman, Tessa, additional, Verploegen, Sandra, additional, Korthouwer, Rianne, additional, van der Wilk, Berend J., additional, Parren, Paul W. H. I., additional, van der Vliet, Hans J., additional, Bögels, Marijn, additional, and van Egmond, Marjolein, additional

Published
2022
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34. IgA EGFR antibodies mediate tumour killing in vivo

Author

Boross, Peter, Lohse, Stefan, Nederend, Maaike, Jansen, Johannes Hendrik Marco, van Tetering, Geert, Dechant, Michael, Peipp, Matthias, Royle, Louise, Liew, Li Phing, Boon, Louis, van Rooijen, Nico, Bleeker, Wim K., Parren, Paul W. H. I., van de Winkel, Jan G. J., Valerius, Thomas, and Leusen, Jeanette H. W.

Published
2013
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36. Bispecific Vγ9Vδ2-T and Type 1 NKT Cell Engager Lava-051 As First-in-Class Clinical Candidate to Target CD1d Expressing CLL, MM and AML

Author

Lameris, Roeland, primary, Ruben, Jurjen M, additional, Weerdt, Iris de, additional, Roovers, Rob, additional, van de Donk, Niels W.C.J., additional, Broyl, Annemiek, additional, Kater, Arnon P., additional, Riedl, Thilo, additional, Iglesias, Victoria, additional, Winograd, Benjamin, additional, Adang, Anton EP, additional, de Gruijl, Tanja D., additional, Parren, Paul W. H. I., additional, and Vliet, Hans J. van der, additional

Published
2021
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37. C1q binding to surface-bound IgG is stabilized by C1r2s2 proteases

Author

Structural Biochemistry, Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Sub Structural Biochemistry, Zwarthoff, Seline A., Widmer, Kevin, Kuipers, Annemarie, Strasser, Jürgen, Ruyken, Maartje, Aerts, Piet C., Haas, Carla J. C. de, Ugurlar, Deniz, Boer, Maurits A. den, Vidarsson, Gestur, Strijp, Jos A. G. van, Gros, Piet, Parren, Paul W. H. I., Kessel, Kok P. M. van, Preiner, Johannes, Beurskens, Frank J., Schuurman, Janine, Ricklin, Daniel, Rooijakkers, Suzan H. M., Structural Biochemistry, Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Sub Structural Biochemistry, Zwarthoff, Seline A., Widmer, Kevin, Kuipers, Annemarie, Strasser, Jürgen, Ruyken, Maartje, Aerts, Piet C., Haas, Carla J. C. de, Ugurlar, Deniz, Boer, Maurits A. den, Vidarsson, Gestur, Strijp, Jos A. G. van, Gros, Piet, Parren, Paul W. H. I., Kessel, Kok P. M. van, Preiner, Johannes, Beurskens, Frank J., Schuurman, Janine, Ricklin, Daniel, and Rooijakkers, Suzan H. M.

Published
2021

38. Fc receptor but not complement binding is important in antibody protection against HIV

Author

Hessell, Ann J., Hangartner, Lars, Hunter, Meredith, Havenith, Carin E. G., Beurskens, Frank J., Bakker, Joost M., Lanigan, Caroline M. S., Landucci, Gary, Forthal, Donald N., Parren, Paul W. H. I., Marx, Preston A., and Burton, Dennis R.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Ann J. Hessell [1, 5]; Lars Hangartner [1, 5]; Meredith Hunter [2]; Carin E. G. Havenith [3]; Frank J. Beurskens [3]; Joost M. Bakker [3]; Caroline M. S. Lanigan [...]

Published
2007

40. HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites

Author

Kwong, Peter D., Doyle, Michael L., Casper, David J., Cicala, Claudia, Leavitt, Stephanie A., Majeed, Shahzad, Steenbeke, Tavis D., Venturi, Miro, Chaiken, Irwin, Fung, Michael, Katinger, Hermann, Parren, Paul W. I. H., Robinson, James, Van Ryk, Donald, Wang, Liping, Burton, Dennis R., Freire, Ernesto, Wyatt, Richard, Sodroski, Joseph, Hendrickson, Wayne A., and Arthos, James

Abstract

Author(s): Peter D. Kwong (corresponding author) [1, 2]; Michael L. Doyle [3, 4]; David J. Casper [3]; Claudia Cicala [5]; Stephanie A. Leavitt [6]; Shahzad Majeed [1, 2]; Tavis D. [...]

Published
2002
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42. Abstract 4544: Multifaceted mechanism of action of DuoHexaBody-CD37 involves both complement- and Fc gamma receptor-mediated cytotoxicity in pre-clinical B-cell lymphoma models

Author

Kil, Laurens P., primary, Oostindie, Simone C., additional, Strumane, Kristin, additional, van der Horst, Hilma J., additional, van Kessel, Berris, additional, Overdijk, Marije B., additional, Lingnau, Andreas, additional, Brandhorst, Marcel, additional, van den Brakel, Jeroen, additional, Lindorfer, Margaret A., additional, Taylor, Ronald P., additional, Chamuleau, Martine E., additional, Mutis, Tuna, additional, Sasser, A. Kate, additional, Schuurman, Janine, additional, Parren, Paul W., additional, Beurskens, Frank J., additional, and Breij, Esther C., additional

Published
2020
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43. A structure-based approach to a synthetic vaccine for HIV-1

Author

Cabezas, Edelmira, Wang, Meng, Parren, Paul W. H. I., Stanfield, Robyn L., and Satterthwait, Arnold C.

Subjects
Biochemistry -- Research, Synthetic vaccines -- Physiological aspects, HIV infection -- Causes of, Peptides -- Research, Antibodies -- Physiological aspects, Proteins -- Research, Biological sciences, Chemistry
Abstract

Research has been conducted on the neutralizing antibodies by peptide immunization. The approaches necessary for developing conformational mimics of protein neutralization sites have been investigated.

Published
2000

46. Unraveling the Macromolecular Pathways of IgG Oligomerization and Complement Activation on Antigenic Surfaces

Author

Strasser, Jürgen, de Jong, Rob N, Beurskens, Frank J, Wang, Guanbo, Heck, Albert J R, Schuurman, Janine, Parren, Paul W H I, Hinterdorfer, Peter, Preiner, Johannes, Sub Biomol.Mass Spectrometry & Proteom., Afd Biomol.Mass Spect. and Proteomics, and Biomolecular Mass Spectrometry and Proteomics

Subjects
C1, high-speed atomic force microscopy, native mass spectrometry, IgG hexamers, immune complex formation, IgG aligomerization, classical complement pathway
Abstract

IgG antibodies play a central role in protection against pathogens by their ability to alert and activate the innate immune system. Here, we show that IgGs assemble into oligomers on antigenic surfaces through an ordered, Fc domain-mediated process that can be modulated by protein engineering. Using high-speed atomic force microscopy, we unraveled the molecular events of IgG oligomer formation on surfaces. IgG molecules were recruited from solution although assembly of monovalently binding molecules also occurred through lateral diffusion. Monomers were observed to assemble into hexamers with all intermediates detected, but in which only hexamers bound C1. Functional characterization of oligomers on cells also demonstrated that C1 binding to IgG hexamers was a prerequisite for maximal activation, whereas tetramers, trimers, and dimers were mostly inactive. We present a dynamic IgG oligomerization model, which provides a framework for exploiting the macromolecular assembly of IgGs on surfaces for tool, immunotherapy, and vaccine design.

Published
2019

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