A Therapeutic Antibody for Cancer, Derived from Single Human B Cells

Bushey, Ryan T.; Moody, M. Anthony; Nicely, Nathan L.; Haynes, Barton F.; Alam, S. Munir; Keir, Stephen T.; Bentley, Rex C.; Roy Choudhury, Kingshuk; Gottlin, Elizabeth B.; Campa, Michael J.; Liao, Hua-Xin; Patz, Jr., Edward F.

doi:10.1016/j.celrep.2016.04.038

Title: A Therapeutic Antibody for Cancer, Derived from Single Human B Cells

Journal Article · Sun May 01 00:00:00 EDT 2016 · Cell Reports

DOI:https://doi.org/10.1016/j.celrep.2016.04.038· OSTI ID:1325319

Bushey, Ryan T.; Moody, M. Anthony; Nicely, Nathan L.; Haynes, Barton F.; Alam, S. Munir; Keir, Stephen T.; Bentley, Rex C.; Roy Choudhury, Kingshuk; Gottlin, Elizabeth B.; Campa, Michael J.; Liao, Hua-Xin; Patz, Jr., Edward F.

Some patients with cancer never develop metastasis, and their host response might provide cues for innovative treatment strategies. We previously reported an association between autoantibodies against complement factor H (CFH) and early-stage lung cancer. CFH prevents complement-mediated cytotoxicity (CDC) by inhibiting formation of cell-lytic membrane attack complexes on self-surfaces. In an effort to translate these findings into a biologic therapy for cancer, we isolated and expressed DNA sequences encoding high-affinity human CFH antibodies directly from single, sorted B cells obtained from patients with the antibody. The co-crystal structure of a CFH antibody-target complex shows a conformational change in the target relative to the native structure. This recombinant CFH antibody causes complement activation and release of anaphylatoxins, promotes CDC of tumor cell lines, and inhibits tumor growth in vivo. The isolation of anti-tumor antibodies derived from single human B cells represents an alternative paradigm in antibody drug discovery.

View Journal Article

Cite

Export

Save

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); LUNGevity Foundation, the Dept. of Defense; National Institutes of Health (NIH)

Grant/Contract Number:: W-31-109-Eng-38; W81XWH-13-1-0189; UL1TR001117

OSTI ID:: 1325319

Alternate ID(s):: OSTI ID: 1256369

Journal Information:: Cell Reports, Journal Name: Cell Reports Vol. 15 Journal Issue: 7; ISSN 2211-1247

Publisher:: ElsevierCopyright Statement

Country of Publication:: Netherlands

Language:: English

Citation Metrics:

Cited by: 28 works

Citation information provided by
Web of Science

References (32)

Structural Analysis of the C-Terminal Region (Modules 18–20) of Complement Regulator Factor H (FH) Morgan, Hugh P.; Mertens, Haydyn D. T.; Guariento, Mara PLoS ONE, Vol. 7, Issue 2 https://doi.org/10.1371/journal.pone.0032187	journal	February 2012
Functional Anatomy of Complement Factor H Makou, Elisavet; Herbert, Andrew P.; Barlow, Paul N. Biochemistry, Vol. 52, Issue 23 https://doi.org/10.1021/bi4003452	journal	May 2013
Complement control protein factor H: The good, the bad, and the inadequate Ferreira, Viviana P.; Pangburn, Michael K.; Cortés, Claudio Molecular Immunology, Vol. 47, Issue 13 https://doi.org/10.1016/j.molimm.2010.05.007	journal	August 2010
Complement Is a Central Mediator of Radiotherapy-Induced Tumor-Specific Immunity and Clinical Response Surace, Laura; Lysenko, Veronika; Fontana, Andrea Orlando Immunity, Vol. 42, Issue 4 https://doi.org/10.1016/j.immuni.2015.03.009	journal	April 2015
Iterative model building, structure refinement and density modification with the PHENIX AutoBuild wizard Terwilliger, Thomas C.; Grosse-Kunstleve, Ralf W.; Afonine, Pavel V. Acta Crystallographica Section D Biological Crystallography, Vol. 64, Issue 1 https://doi.org/10.1107/S090744490705024X	journal	December 2007
Crystal Structure of the Calcium-stabilized Human Factor IX Gla Domain Bound to a Conformation-specific Anti-factor IX Antibody Huang, Mingdong; Furie, Barbara C.; Furie, Bruce Journal of Biological Chemistry, Vol. 279, Issue 14 https://doi.org/10.1074/jbc.M314011200	journal	April 2004
Complement Factor H Antibodies from Lung Cancer Patients Induce Complement-Dependent Lysis of Tumor Cells, Suggesting a Novel Immunotherapeutic Strategy Campa, Michael J.; Gottlin, Elizabeth B.; Bushey, Ryan T. Cancer Immunology Research, Vol. 3, Issue 12 https://doi.org/10.1158/2326-6066.CIR-15-0122	journal	July 2015
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Complement Factor H-Antibody–Associated Hemolytic Uremic Syndrome: Pathogenesis, Clinical Presentation, and Treatment Hofer, Johannes; Giner, Thomas; Józsi, Mihály Seminars in Thrombosis and Hemostasis, Vol. 40, Issue 04 https://doi.org/10.1055/s-0034-1375297	journal	May 2014
Complement Factor H Autoantibodies Are Associated with Early Stage NSCLC Amornsiripanitch, Nita; Hong, Shaolin; Campa, Michael J. Clinical Cancer Research, Vol. 16, Issue 12 https://doi.org/10.1158/1078-0432.CCR-10-0321	journal	June 2010
Structure validation by Cα geometry: ϕ,ψ and Cβ deviation Lovell, Simon C.; Davis, Ian W.; Arendall, W. Bryan Proteins: Structure, Function, and Bioinformatics, Vol. 50, Issue 3 https://doi.org/10.1002/prot.10286	journal	January 2003
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Exceptional Resistance of Human H2 Glioblastoma Cells to Complement-Mediated Killing by Expression and Utilization of Factor H and Factor H-Like Protein 1 Junnikkala, S.; Jokiranta, T. S.; Friese, M. A. The Journal of Immunology, Vol. 164, Issue 11 https://doi.org/10.4049/jimmunol.164.11.6075	journal	June 2000
Sequence of a human immunoglobulin gamma 3 heavy chain constant region gene: comparison with the other human C _γ genes Huck, S.; Fort, P.; Crawford, D. H. Nucleic Acids Research, Vol. 14, Issue 4 https://doi.org/10.1093/nar/14.4.1779	journal	January 1986
Reconstructing a B-Cell Clonal Lineage. II. Mutation, Selection, and Affinity Maturation Kepler, Thomas B.; Munshaw, Supriya; Wiehe, Kevin Frontiers in Immunology, Vol. 5 https://doi.org/10.3389/fimmu.2014.00170	journal	April 2014
Structural and Functional Characterization of the Product of Disease-Related Factor H Gene Conversion Herbert, Andrew P.; Kavanagh, David; Johansson, Conny Biochemistry, Vol. 51, Issue 9 https://doi.org/10.1021/bi201689j	journal	February 2012
Reconstructing a B-cell clonal lineage. I. Statistical inference of unobserved ancestors Kepler, Thomas B. F1000Research, Vol. 2 https://doi.org/10.12688/f1000research.2-103.v1	journal	January 2013
Initial antibodies binding to HIV-1 gp41 in acutely infected subjects are polyreactive and highly mutated Liao, Hua-Xin; Chen, Xi; Munshaw, Supriya The Journal of Experimental Medicine, Vol. 208, Issue 11 https://doi.org/10.1084/jem.20110363	journal	October 2011
Cytolysis of nucleated cells by complement: cell death displays multi-hit characteristics. Koski, C. L.; Ramm, L. E.; Hammer, C. H. Proceedings of the National Academy of Sciences, Vol. 80, Issue 12 https://doi.org/10.1073/pnas.80.12.3816	journal	June 1983
The possible role of factor H in colon cancer resistance to complement attack Wilczek, Ewa; Rzepko, Robert; Nowis, Dominika International Journal of Cancer, Vol. 122, Issue 9 https://doi.org/10.1002/ijc.23238	journal	January 2008
The complete amino acid sequence of a mouse ϰ light chain Svasti, J.; Milstein, C. Biochemical Journal, Vol. 128, Issue 2 https://doi.org/10.1042/bj1280427	journal	June 1972
Crystal structure of a non-neutralizing antibody to the HIV-1 gp41 membrane-proximal external region Nicely, Nathan I.; Dennison, S. Moses; Spicer, Leonard Nature Structural & Molecular Biology, Vol. 17, Issue 12 https://doi.org/10.1038/nsmb.1944	journal	November 2010
High-throughput isolation of immunoglobulin genes from single human B cells and expression as monoclonal antibodies Liao, Hua-Xin; Levesque, Marc C.; Nagel, Ashleigh Journal of Virological Methods, Vol. 158, Issue 1-2 https://doi.org/10.1016/j.jviromet.2009.02.014	journal	June 2009
Human lung cancer cell lines express cell membrane complement inhibitory proteins and are extremely resistant to complement-mediated lysis; a comparison with normal human respiratory epitheliumin vitro, and an insight into mechanism(s) of resistance Varsano, S.; Rashkovsky, L.; Shapiro, H. Clinical and Experimental Immunology, Vol. 113, Issue 2, p. 173-182 https://doi.org/10.1046/j.1365-2249.1998.00581.x	journal	December 2001
The role of the anaphylatoxins in health and disease Klos, Andreas; Tenner, Andrea J.; Johswich, Kay-Ole Molecular Immunology, Vol. 46, Issue 14 https://doi.org/10.1016/j.molimm.2009.04.027	journal	September 2009
Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus Liao, Hua-Xin; Lynch, Rebecca; Zhou, Tongqing Nature, Vol. 496, Issue 7446 https://doi.org/10.1038/nature12053	journal	April 2013
Dual interaction of factor H with C3d and glycosaminoglycans in host-nonhost discrimination by complement Kajander, T.; Lehtinen, M. J.; Hyvarinen, S. Proceedings of the National Academy of Sciences, Vol. 108, Issue 7 https://doi.org/10.1073/pnas.1017087108	journal	February 2011
Structural basis for engagement by complement factor H of C3b on a self surface Morgan, Hugh P.; Schmidt, Christoph Q.; Guariento, Mara Nature Structural & Molecular Biology, Vol. 18, Issue 4 https://doi.org/10.1038/nsmb.2018	journal	February 2011
Crystal structure of human germline antibody 3-23/B3 Malia, Thomas J.; Obmolova, Galina; Almagro, Juan Carlos Molecular Immunology, Vol. 48, Issue 12-13 https://doi.org/10.1016/j.molimm.2011.04.020	journal	July 2011
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
Down-Regulation of Human Complement Factor H Sensitizes Non-Small Cell Lung Cancer Cells to Complement Attack and Reduces In Vivo Tumor Growth Ajona, Daniel; Hsu, Yi-Fan; Corrales, Leticia The Journal of Immunology, Vol. 178, Issue 9 https://doi.org/10.4049/jimmunol.178.9.5991	journal	April 2007
Isolation of a Human Anti-HIV gp41 Membrane Proximal Region Neutralizing Antibody by Antigen-Specific Single B Cell Sorting Morris, Lynn; Chen, Xi; Alam, Munir PLoS ONE, Vol. 6, Issue 9 https://doi.org/10.1371/journal.pone.0023532	journal	September 2011

Similar Records

Human peripheral blood monocytes display surface antigens recognized by monoclonal antinuclear antibodies

Journal Article · Sun Sep 01 00:00:00 EDT 1985 · J. Clin. Invest.; (United States) · OSTI ID:1325319

Holers, V M; Kotzin, B L

Effects of amino acid substitutions on the biological activity of anti-CD20 monoclonal antibody produced by transgenic silkworms (Bombyx mori)

Journal Article · Sat Sep 15 00:00:00 EDT 2018 · Biochemical and Biophysical Research Communications · OSTI ID:1325319

Aoyama, Michihiko; Tada, Minoru; Tatematsu, Ken-Ichiro; +3 more

Regulation of IL-2 induced proliferation and cytotoxicity in human natural killer cells by monoclonal antibodies

Conference · Wed Mar 05 00:00:00 EST 1986 · Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States) · OSTI ID:1325319

Mason, A T; Ortaldo, J R

Related Subjects

60 APPLIED LIFE SCIENCES

Title: A Therapeutic Antibody for Cancer, Derived from Single Human B Cells

Citation Formats

References (32)

Similar Records

Related Subjects