Human igg1 antibodies suppress angiogenesis in a target-independent manner

Sasha Bogdanovich; Younghee Kim; Takeshi Mizutani; Reo Yasuma; Laura Tudisco; Valeria Cicatiello; Ana Bastos-Carvalho; Nagaraj Kerur; Yoshio Hirano; Judit Z. Baffi; Valeria Tarallo; Shengjian Li; Tetsuhiro Yasuma; Parthasarathy Arpitha; Benjamin J. Fowler; Charles B. Wright; Ivana Apicella; Adelaide Greco; Arturo Brunetti; Menotti Ruvo; Annamaria Sandomenico; Miho Nozaki; Ryo Ijima; Hiroki Kaneko; Yuichiro Ogura; Hiroko Terasaki; Balamurali K. Ambati; Jeanette H.W. Leusen; Wallace Y. Langdon; Michael R. Clark; Kathryn L. Armour; Pierre Bruhns; J. Sjef Verbeek; Bradley D. Gelfand; Sandro De Falco; Jayakrishna Ambati

doi:10.1038/sigtrans.2015.1

Human igg1 antibodies suppress angiogenesis in a target-independent manner

Sasha Bogdanovich, Younghee Kim, Takeshi Mizutani, Reo Yasuma, Laura Tudisco, Valeria Cicatiello, Ana Bastos-Carvalho, Nagaraj Kerur, Yoshio Hirano, Judit Z. Baffi, Valeria Tarallo, Shengjian Li, Tetsuhiro Yasuma, Parthasarathy Arpitha, Benjamin J. Fowler, Charles B. Wright, Ivana Apicella, Adelaide Greco, Arturo Brunetti, Menotti RuvoAnnamaria Sandomenico, Miho Nozaki, Ryo Ijima, Hiroki Kaneko, Yuichiro Ogura, Hiroko Terasaki, Balamurali K. Ambati, Jeanette H.W. Leusen, Wallace Y. Langdon, Michael R. Clark, Kathryn L. Armour, Pierre Bruhns, J. Sjef Verbeek, Bradley D. Gelfand, Sandro De Falco, Jayakrishna Ambati

Opthalmology

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world’s population. The most widely used anti-angiogenic drug is bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits angiogenesis in mice. Here we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI (CD64) and c-Cbl, impairing macrophage migration. Other approved humanized or human IgG1 antibodies without mouse targets (adalimumab, alemtuzumab, ofatumumab, omalizumab, palivizumab and tocilizumab), mouse IgG2a, and overexpression of human IgG1-Fc or mouse IgG2a-Fc, also inhibited angiogenesis in wild-type and FcγR humanized mice. This anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown, Fc cleavage, IgG-Fc inhibition, disruption of Fc-FcγR interaction, or elimination of FcRγ-initated signaling. Furthermore, bevacizumab’s Fc region potentiated its anti-angiogenic activity in humanized VEGFA mice. Finally, mice deficient in FcγRI exhibited increased developmental and pathological angiogenesis. These findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies.

Original language	English
Article number	15001
Journal	Signal Transduction and Targeted Therapy
Volume	1
DOIs	https://doi.org/10.1038/sigtrans.2015.1
State	Published - 2016

Bibliographical note

Funding Information:
JA is a co-founder of iVeena Holdings, iVeena Pharmaceuticals, iVeena Delivery Systems and Inflammasome Therapeutics, and has received honoraria from Allergan and research funding from Olix Pharmaceuticals unrelated to this work. JA and SDF are named as inventors on patent applications filed by the University of Kentucky relating to the technology described in this work. MRC is listed as an inventor on patents covering alemtuzumab and MRC and KLA are listed as inventors on patents covering the Fc mutated forms of alemtuzumab.

Funding Information:
We thank T.S. Khurana, S. Bondada, K. Ambati, A.M. Rao and G.S. Rao for discussions; L. Toll, G.R. Pattison R. King, L. Xu, M. McConnell, C. Payne, D. Robertson, G. Botzet, A. Uiettenbogaard and the IGB animal house and integrated microscopy facilities, for technical assistance. We thank J.V. Ravetch and N. Ferrara for generously sharing genetically modified mice. JA was supported by NIH grants DP1GM114862, R01EY018350, R01EY018836, R01EY020672, R01EY022238, R01EY024068, R21EY019778 and RC1EY020442, Doris Duke Distinguished Clinical Scientist Award, Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, Ellison Medical Foundation Senior Scholar in Aging Award, Foundation Fighting Blindness Individual Investigator Research Award, Carl Marshall Reeves Foundation, Harrington Discovery Institute Scholar-Innovator Award, John Templeton Foundation, Dr E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair, and Research to Prevent Blindness departmental unrestricted grant; SDF by Associazione Italiana Ricerca sul Cancro (AIRC) grant no. IG11420 and Italian Ministry for Scientific Research, projects PON01_02342 and PON01_01434; MR and AS by Italian Ministry for Scientific Research, grants FIRB MERIT N° RBNE08NKH7_003 and PON01_01602, PON01_02342. JZB by NIH K08EY021521 and University of Kentucky Physician Scientist Award; BJF and SB by NIH T32HL091812 and UL1RR033173; YH by Alcon Research Award; AB-C by the Program for Advanced Medical Education (sponsored by Fundação Calouste Gulbenkian, Fundação Champalimaud, Ministério da Saúde and Fundação para a Ciência e Tecnologia, Portugal) and Bayer Global Ophthalmology Research Award; YH by Alcon Japan Research award; NK by Beckman Initiative for Macular Research and NIH K99/R00EY024336; TY by Fight for Sight Postdoctoral Award; CBW by International Retinal Research Foundation; BDG by American Heart Association and International Retinal Research Foundation; BKA by NIH R01EY017182 and R01EY017950, VA Merit Award, and Department of Defense.

Publisher Copyright:
© 2016 West China Hospital, Sichuan University.

ASJC Scopus subject areas

Genetics
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/sigtrans.2015.1

Cite this

Bogdanovich, S., Kim, Y., Mizutani, T., Yasuma, R., Tudisco, L., Cicatiello, V., Bastos-Carvalho, A., Kerur, N., Hirano, Y., Baffi, J. Z., Tarallo, V., Li, S., Yasuma, T., Arpitha, P., Fowler, B. J., Wright, C. B., Apicella, I., Greco, A., Brunetti, A., ... Ambati, J. (2016). Human igg1 antibodies suppress angiogenesis in a target-independent manner. Signal Transduction and Targeted Therapy, 1, Article 15001. https://doi.org/10.1038/sigtrans.2015.1

@article{0b71c147ae424fdb86ed81aeb46d6754,

title = "Human igg1 antibodies suppress angiogenesis in a target-independent manner",

abstract = "Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world{\textquoteright}s population. The most widely used anti-angiogenic drug is bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits angiogenesis in mice. Here we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI (CD64) and c-Cbl, impairing macrophage migration. Other approved humanized or human IgG1 antibodies without mouse targets (adalimumab, alemtuzumab, ofatumumab, omalizumab, palivizumab and tocilizumab), mouse IgG2a, and overexpression of human IgG1-Fc or mouse IgG2a-Fc, also inhibited angiogenesis in wild-type and FcγR humanized mice. This anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown, Fc cleavage, IgG-Fc inhibition, disruption of Fc-FcγR interaction, or elimination of FcRγ-initated signaling. Furthermore, bevacizumab{\textquoteright}s Fc region potentiated its anti-angiogenic activity in humanized VEGFA mice. Finally, mice deficient in FcγRI exhibited increased developmental and pathological angiogenesis. These findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies.",

author = "Sasha Bogdanovich and Younghee Kim and Takeshi Mizutani and Reo Yasuma and Laura Tudisco and Valeria Cicatiello and Ana Bastos-Carvalho and Nagaraj Kerur and Yoshio Hirano and Baffi, {Judit Z.} and Valeria Tarallo and Shengjian Li and Tetsuhiro Yasuma and Parthasarathy Arpitha and Fowler, {Benjamin J.} and Wright, {Charles B.} and Ivana Apicella and Adelaide Greco and Arturo Brunetti and Menotti Ruvo and Annamaria Sandomenico and Miho Nozaki and Ryo Ijima and Hiroki Kaneko and Yuichiro Ogura and Hiroko Terasaki and Ambati, {Balamurali K.} and Leusen, {Jeanette H.W.} and Langdon, {Wallace Y.} and Clark, {Michael R.} and Armour, {Kathryn L.} and Pierre Bruhns and Verbeek, {J. Sjef} and Gelfand, {Bradley D.} and {De Falco}, Sandro and Jayakrishna Ambati",

note = "Funding Information: JA is a co-founder of iVeena Holdings, iVeena Pharmaceuticals, iVeena Delivery Systems and Inflammasome Therapeutics, and has received honoraria from Allergan and research funding from Olix Pharmaceuticals unrelated to this work. JA and SDF are named as inventors on patent applications filed by the University of Kentucky relating to the technology described in this work. MRC is listed as an inventor on patents covering alemtuzumab and MRC and KLA are listed as inventors on patents covering the Fc mutated forms of alemtuzumab. Funding Information: We thank T.S. Khurana, S. Bondada, K. Ambati, A.M. Rao and G.S. Rao for discussions; L. Toll, G.R. Pattison R. King, L. Xu, M. McConnell, C. Payne, D. Robertson, G. Botzet, A. Uiettenbogaard and the IGB animal house and integrated microscopy facilities, for technical assistance. We thank J.V. Ravetch and N. Ferrara for generously sharing genetically modified mice. JA was supported by NIH grants DP1GM114862, R01EY018350, R01EY018836, R01EY020672, R01EY022238, R01EY024068, R21EY019778 and RC1EY020442, Doris Duke Distinguished Clinical Scientist Award, Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, Ellison Medical Foundation Senior Scholar in Aging Award, Foundation Fighting Blindness Individual Investigator Research Award, Carl Marshall Reeves Foundation, Harrington Discovery Institute Scholar-Innovator Award, John Templeton Foundation, Dr E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair, and Research to Prevent Blindness departmental unrestricted grant; SDF by Associazione Italiana Ricerca sul Cancro (AIRC) grant no. IG11420 and Italian Ministry for Scientific Research, projects PON01_02342 and PON01_01434; MR and AS by Italian Ministry for Scientific Research, grants FIRB MERIT N° RBNE08NKH7_003 and PON01_01602, PON01_02342. JZB by NIH K08EY021521 and University of Kentucky Physician Scientist Award; BJF and SB by NIH T32HL091812 and UL1RR033173; YH by Alcon Research Award; AB-C by the Program for Advanced Medical Education (sponsored by Funda{\c c}{\~a}o Calouste Gulbenkian, Funda{\c c}{\~a}o Champalimaud, Minist{\'e}rio da Sa{\'u}de and Funda{\c c}{\~a}o para a Ci{\^e}ncia e Tecnologia, Portugal) and Bayer Global Ophthalmology Research Award; YH by Alcon Japan Research award; NK by Beckman Initiative for Macular Research and NIH K99/R00EY024336; TY by Fight for Sight Postdoctoral Award; CBW by International Retinal Research Foundation; BDG by American Heart Association and International Retinal Research Foundation; BKA by NIH R01EY017182 and R01EY017950, VA Merit Award, and Department of Defense. Publisher Copyright: {\textcopyright} 2016 West China Hospital, Sichuan University.",

year = "2016",

doi = "10.1038/sigtrans.2015.1",

language = "English",

volume = "1",

}

Bogdanovich, S, Kim, Y, Mizutani, T, Yasuma, R, Tudisco, L, Cicatiello, V, Bastos-Carvalho, A, Kerur, N, Hirano, Y, Baffi, JZ, Tarallo, V, Li, S, Yasuma, T, Arpitha, P, Fowler, BJ, Wright, CB, Apicella, I, Greco, A, Brunetti, A, Ruvo, M, Sandomenico, A, Nozaki, M, Ijima, R, Kaneko, H, Ogura, Y, Terasaki, H, Ambati, BK, Leusen, JHW, Langdon, WY, Clark, MR, Armour, KL, Bruhns, P, Verbeek, JS, Gelfand, BD, De Falco, S & Ambati, J 2016, 'Human igg1 antibodies suppress angiogenesis in a target-independent manner', Signal Transduction and Targeted Therapy, vol. 1, 15001. https://doi.org/10.1038/sigtrans.2015.1

TY - JOUR

T1 - Human igg1 antibodies suppress angiogenesis in a target-independent manner

AU - Bogdanovich, Sasha

AU - Kim, Younghee

AU - Mizutani, Takeshi

AU - Yasuma, Reo

AU - Tudisco, Laura

AU - Cicatiello, Valeria

AU - Bastos-Carvalho, Ana

AU - Kerur, Nagaraj

AU - Hirano, Yoshio

AU - Baffi, Judit Z.

AU - Tarallo, Valeria

AU - Li, Shengjian

AU - Yasuma, Tetsuhiro

AU - Arpitha, Parthasarathy

AU - Fowler, Benjamin J.

AU - Wright, Charles B.

AU - Apicella, Ivana

AU - Greco, Adelaide

AU - Brunetti, Arturo

AU - Ruvo, Menotti

AU - Sandomenico, Annamaria

AU - Nozaki, Miho

AU - Ijima, Ryo

AU - Kaneko, Hiroki

AU - Ogura, Yuichiro

AU - Terasaki, Hiroko

AU - Ambati, Balamurali K.

AU - Leusen, Jeanette H.W.

AU - Langdon, Wallace Y.

AU - Clark, Michael R.

AU - Armour, Kathryn L.

AU - Bruhns, Pierre

AU - Verbeek, J. Sjef

AU - Gelfand, Bradley D.

AU - De Falco, Sandro

AU - Ambati, Jayakrishna

N1 - Funding Information: JA is a co-founder of iVeena Holdings, iVeena Pharmaceuticals, iVeena Delivery Systems and Inflammasome Therapeutics, and has received honoraria from Allergan and research funding from Olix Pharmaceuticals unrelated to this work. JA and SDF are named as inventors on patent applications filed by the University of Kentucky relating to the technology described in this work. MRC is listed as an inventor on patents covering alemtuzumab and MRC and KLA are listed as inventors on patents covering the Fc mutated forms of alemtuzumab. Funding Information: We thank T.S. Khurana, S. Bondada, K. Ambati, A.M. Rao and G.S. Rao for discussions; L. Toll, G.R. Pattison R. King, L. Xu, M. McConnell, C. Payne, D. Robertson, G. Botzet, A. Uiettenbogaard and the IGB animal house and integrated microscopy facilities, for technical assistance. We thank J.V. Ravetch and N. Ferrara for generously sharing genetically modified mice. JA was supported by NIH grants DP1GM114862, R01EY018350, R01EY018836, R01EY020672, R01EY022238, R01EY024068, R21EY019778 and RC1EY020442, Doris Duke Distinguished Clinical Scientist Award, Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, Ellison Medical Foundation Senior Scholar in Aging Award, Foundation Fighting Blindness Individual Investigator Research Award, Carl Marshall Reeves Foundation, Harrington Discovery Institute Scholar-Innovator Award, John Templeton Foundation, Dr E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair, and Research to Prevent Blindness departmental unrestricted grant; SDF by Associazione Italiana Ricerca sul Cancro (AIRC) grant no. IG11420 and Italian Ministry for Scientific Research, projects PON01_02342 and PON01_01434; MR and AS by Italian Ministry for Scientific Research, grants FIRB MERIT N° RBNE08NKH7_003 and PON01_01602, PON01_02342. JZB by NIH K08EY021521 and University of Kentucky Physician Scientist Award; BJF and SB by NIH T32HL091812 and UL1RR033173; YH by Alcon Research Award; AB-C by the Program for Advanced Medical Education (sponsored by Fundação Calouste Gulbenkian, Fundação Champalimaud, Ministério da Saúde and Fundação para a Ciência e Tecnologia, Portugal) and Bayer Global Ophthalmology Research Award; YH by Alcon Japan Research award; NK by Beckman Initiative for Macular Research and NIH K99/R00EY024336; TY by Fight for Sight Postdoctoral Award; CBW by International Retinal Research Foundation; BDG by American Heart Association and International Retinal Research Foundation; BKA by NIH R01EY017182 and R01EY017950, VA Merit Award, and Department of Defense. Publisher Copyright: © 2016 West China Hospital, Sichuan University.

PY - 2016

Y1 - 2016

N2 - Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world’s population. The most widely used anti-angiogenic drug is bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits angiogenesis in mice. Here we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI (CD64) and c-Cbl, impairing macrophage migration. Other approved humanized or human IgG1 antibodies without mouse targets (adalimumab, alemtuzumab, ofatumumab, omalizumab, palivizumab and tocilizumab), mouse IgG2a, and overexpression of human IgG1-Fc or mouse IgG2a-Fc, also inhibited angiogenesis in wild-type and FcγR humanized mice. This anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown, Fc cleavage, IgG-Fc inhibition, disruption of Fc-FcγR interaction, or elimination of FcRγ-initated signaling. Furthermore, bevacizumab’s Fc region potentiated its anti-angiogenic activity in humanized VEGFA mice. Finally, mice deficient in FcγRI exhibited increased developmental and pathological angiogenesis. These findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies.

AB - Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world’s population. The most widely used anti-angiogenic drug is bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits angiogenesis in mice. Here we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI (CD64) and c-Cbl, impairing macrophage migration. Other approved humanized or human IgG1 antibodies without mouse targets (adalimumab, alemtuzumab, ofatumumab, omalizumab, palivizumab and tocilizumab), mouse IgG2a, and overexpression of human IgG1-Fc or mouse IgG2a-Fc, also inhibited angiogenesis in wild-type and FcγR humanized mice. This anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown, Fc cleavage, IgG-Fc inhibition, disruption of Fc-FcγR interaction, or elimination of FcRγ-initated signaling. Furthermore, bevacizumab’s Fc region potentiated its anti-angiogenic activity in humanized VEGFA mice. Finally, mice deficient in FcγRI exhibited increased developmental and pathological angiogenesis. These findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies.

UR - http://www.scopus.com/inward/record.url?scp=85009106495&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85009106495&partnerID=8YFLogxK

U2 - 10.1038/sigtrans.2015.1

DO - 10.1038/sigtrans.2015.1

M3 - Article

AN - SCOPUS:85009106495

SN - 2095-9907

VL - 1

JO - Signal Transduction and Targeted Therapy

JF - Signal Transduction and Targeted Therapy

M1 - 15001

ER -

Human igg1 antibodies suppress angiogenesis in a target-independent manner

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this