Development of a panel of neutralizing monoclonal antibodies aiming toward HIV cure

• Project/Area Number: 24591484
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Infectious disease medicine
• Research Institution: Kumamoto University
• Principal Investigator: MATSUSHITA Shuzo 熊本大学, エイズ学研究センター, 教授 (00199788)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: HIV-1 / エンベロープ蛋白 / 交差中和抗体 / ADCC / 免疫学 / ウイルス / 感染防御学 / 中和抗体 / 動物モデル

Outline of Final Research Achievements

HIV-1infection/AIDS became a controllable disease following continuous advancement of combination antiretroviral therapy (cART). However, pathogenic process that is caused by residual viral replication under effective cART has been noticed as a major problem in the long-term control of HIV-1 infected patients. In this study we established assay system to measure antibody-dependent cell-mediated cytotoxicity (ADCC) aiming toward elimination of HIV-1 infected cell using a panel of neutralizing monoclonal antibodies and identified the antibody response that is effective for ADCC. We also found a patient who had broad neutralizing activity against 22 pseudoviruses of 7 different subtypes and identified epitope recognized by the antiserum in V2/V3 region of gp120.

Research Products

• [Journal Article] Passive transfer of neutralizing monoclonal antibody KD-247reduces plasma viral load in patients chronically infected with HIV-1. (2015)
  • Author(s): Matsushita, S., Yoshimura, K., Ramirez, K.P., Pisupati, J., Murakami, T.
  • Journal Title: AIDS Volume: 29 Issue: 4 Pages: 453-462
  • DOI: 10.1097/qad.0000000000000570
  • Peer Reviewed
• [Journal Article] Complementary and synergistic activities of anti-V3, CD4bs and CD4i antibodies derived from a single individual can cover a wide range of HIV-1 strains. (2015)
  • Author(s): Ramirez, K.P., Kuwata, T., Maruta, Y, Tanaka K., Muntasir, A., Yoshimura, K., Matsushita, S.
  • Journal Title: Virology Volume: 475 Pages: 187-203
  • DOI: 10.1016/j.virol.2014.11.011
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Structural basis of clade-specific HIV-1 neutralization by humanized anti-V3 monoclonal antibody KD-247. (2015)
  • Author(s): Kirby, K.A., Ong Y.T., Hachiya, A., Laughlin, T.G.,Chiang, L.A., Pan Y., Moran, J.L., Marchand, B.,Singh, K., Gallazzi, F., Quinn, T.P., Yoshimura, K., Murakami, T., Matsushita S., Sarafianos, S.G.
  • Journal Title: The FASEB Journal Volume: 29 Issue: 1 Pages: 1-11
  • DOI: 10.1096/fj.14-252262
  • Peer Reviewed / Open Access
• [Journal Article] Impact of maraviroc-resistant and low-CCR5- adapted mutations induced by in vitro passage on sensitivity to anti-envelope neutralizing antibodies. (2014)
  • Author(s): Kazuhisa Yoshimura, Shigeyoshi Harada, Samatchaya Boonchawalit, Yoko Kawanami, Shuzo Matsushita.
  • Journal Title: Journal of General Virology Volume: 95 Issue: 8 Pages: 1816-1826
  • DOI: 10.1099/vir.0.062885-0
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A CD4 Mimic as an HIV Entry Inhibitors: Pharmacokinetics (2013)
  • Author(s): Hashimoto, C., Narumi, T., Otsuki, H., Hirota, Y., Arai, H., Yoshimura, K., Harada, S., Ohashi, N., Nomura, W., Miura, T., Igarashi, T., Matsuhita, S., Tamamura, H.
  • Journal Title: Bioorg. Med. Chem. Volume: 21 Issue: 24 Pages: 7884-7889
  • DOI: 10.1016/j.bmc.2013.10.005
  • Peer Reviewed
• [Journal Article] Generation of a replication-competent simianhuman immunodeficiency virus, the neutralisation sensitivity of which can be enhanced in the presence of a small molecule CD4 mimic. (2013)
  • Author(s): Otsuki, H., Hishiki, T., Miura, T., Hashimoto, C., Narumi, T., Tamamura, H., Yoshimura, K., Matsushita, S., and Igarashi, T.
  • Journal Title: J. Gen. Virol. Volume: 94 Issue: 12 Pages: 2710-2716
  • DOI: 10.1099/vir.0.055590-0
  • Peer Reviewed
• [Journal Article] Abacavir/Lamivudine versus Tenofovir/Emtricitabine with Atazanavir/Ritonavir for Treatment-naive Japanese Patients with HIV-1 Infection: A Randomized Multicenter Trial (2013)
  • Author(s): Nishijima, T.
  • Journal Title: Internal Medicine Volume: 52 Issue: 7 Pages: 735-744
  • DOI: 10.2169/internalmedicine.52.9155
  • NAID: 130003365967
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed
• [Journal Article] CD4 Mimics as HIV Entry Inhibitors: Lead Optimization Studies of the Aromatic Substituents. (2013)
  • Author(s): Narumi, T., Arai, H., Yoshimura, K., Harada, S., Hirota, Y., Ohashi, N., Hashimoto, C.. Nomura, W., Matsushita, S. and Tamamura, H.
  • Journal Title: Bioorg. Med. Chem. Volume: 8 Issue: 9 Pages: 2518-2526
  • DOI: 10.1016/j.bmc.2013.02.041
  • Peer Reviewed
• [Journal Article] Conformational epitope consisting of the V3 and V4 loops as a target for potent and broad neutralization of simian immunodeficiency viruses. (2013)
  • Author(s): Kuwata T
  • Journal Title: J Virol. Volume: in press Issue: 10 Pages: 933-943
  • DOI: 10.1128/jvi.00201-13
  • Peer Reviewed
• [Journal Article] Increased infectivity in human cells and resistance to antibody-mediated neutralization by truncation of the SIV gp41 cytoplasmic tail. (2013)
  • Author(s): 8. Kuwata, T.
  • Journal Title: Frontiers in Microbiology/Virology. Volume: 4 Pages: 1-7
  • DOI: 10.3389/fmicb.2013.00117
  • Peer Reviewed
• [Journal Article] Impact of antiretroviral pressure on selection of primary human immunodeficiency virus type 1 envelope sequences in vitro. (2013)
  • Author(s): Shigeyoshi Harada, Kazuhisa Yoshimura, Aki Yamaguchi, Samatchaya Boonchawalit, Keisuke Yusa, Shuzo Matsushita.
  • Journal Title: Journal of General Virology Volume: 94 Issue: 5 Pages: 933-943
  • DOI: 10.1099/vir.0.047167-0
  • Peer Reviewed
• [Journal Article] Structural Dynamics of HIV-1 Envelope Gp120 Outer Domain with V3 Loop. (2012)
  • Author(s): Yokoyama M.
  • Journal Title: PLoS ONE Volume: 7 Issue: 5 Pages: 1-9
  • DOI: 10.1371/journal.pone.0037530
  • Peer Reviewed
• [Journal Article] Preparation of Biologically Active Single-Chain Variable Antibody Fragments that Target the HIV-1 gp120 V3 Loop (2012)
  • Author(s): Ong Y.T.
  • Journal Title: Cellular and molecular biology Volume: 58 Pages: 71-79
  • Peer Reviewed
• [Presentation] Enhanced Neutralization of HIV-1 with Fusion Inhibitor Resistant Mutations. The annual Conference on Retroviruses and Opportunistic Infections (CROI 2015). (2015)
  • Author(s): Muntasir, A., Kuwata, T., Ramirez, K., Maruta, Y., Tanaka K., Shimura, K., Oishi, S., Fujii, N., Matsuoka, M., Matsushita, S.
  • Organizer: The annual Conference on Retroviruses and Opportunistic Infections (CROI 2015).
  • Place of Presentation: the Washington State Convention Center(Seattle, Washington, USA.)
  • Year and Date: 2015-02-23 – 2015-02-26
• [Presentation] Therapeutic application of neutralizing antibodies based on the recent data on complementary and synergistic activities against a wide range of HIV-1 strains. (2015)
  • Author(s): Matsushita, S., Ramirez, K.P., Maruta, Y., Tanaka, K., Muntasir, A., Kuwata, T., Pisupait, J., Murakami, T., Yoshimura, K.
  • Organizer: the 17th International Conference on Emerging Infectious Diseases (EID) Emerging Infectious Diseases Meeting
  • Place of Presentation: Building of Humanities and Social Sciences, Academia Sinica(Taipei, Taiwan)
  • Year and Date: 2015-01-26 – 2015-01-27
• [Presentation] Mechanism of post-attachment neutralization of single-chain variable fragment (scFv) from anti-V3 monoclonal antibody with cross-reactivity. (2015)
  • Author(s): Maruta, Y., Kuwata, T., Tanaka, K., Nakahara,Y., Ramirez, K., Alam, M., Egami, Y., Hirata, I., Suwa, Y., Morioka, H., Matsushita, S.
  • Organizer: Korea-Japan Joint Seminar on HIV/AIDS.
  • Place of Presentation: 熊本大学山崎記念会館（熊本市）
  • Year and Date: 2015-01-10
• [Presentation] Complementary effect of anti-V3, CD4bs and CD4i antibodies accounts for cross-neutralizing and non-neutralizing activities against HIV-1. (2014)
  • Author(s): Ramirez, K.P., Kuwata, T., Maruta, Y, Tanaka K., Muntasir, A., Yoshimura, K., Matsushita, S.
  • Organizer: 第28回日本エイズ学会学術集会・総会.
  • Place of Presentation: 大阪国際会議場（大阪市）
  • Year and Date: 2014-12-03 – 2014-12-05
• [Presentation] V3エピトープへの交叉反応性をもつ中和抗体の遺伝子組み換えによる小型化の試み (2014)
  • Author(s): 江上由華、丸田泰広、田中和樹、Muntasir A., Ramirez K., 桑田岳夫、松下修三.
  • Organizer: 第28回日本エイズ学会学術集会・総会.
  • Place of Presentation: 大阪国際会議場（大阪市）
  • Year and Date: 2014-12-03 – 2014-12-05
• [Presentation] Mechanism of post-attachment neutralization of single-chain variable fragment (scFv) from anti-V3 monoclonal antibody against HIV-1 (2014)
  • Author(s): Maruta, Y., Kuwata, T., Tanaka, K., Nakahara,Y., Ramirez, K., Alam, M., Egami, Y., Hirata I., Suwa, Y., Morioka, H., Matsushita, S.
  • Organizer: HIV R4P 2014
  • Place of Presentation: Cape Town International Convention Centre(Cape Town, South Africa)
  • Year and Date: 2014-10-28 – 2014-10-31
• [Presentation] Therapeutic application of neutralizing antibodies based on the recent data on complementary and synergistic activities against a wide range of HIV-1 strains. (2014)
  • Author(s): Matsushita, S., Ramirez, K.P., Maruta, Y., Tanaka, K., Muntasir, A., Kuwata, T., Pisupait, J., Murakami, T., Yoshimura, K.
  • Organizer: 15th Kumamoto AIDS Seminar.
  • Place of Presentation: ホテル日航熊本（熊本市）
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] Evaluation of complementarity and synergy of conventional anti-HIV-1 antibodies derived from a single individual (2014)
  • Author(s): Ramirez, K.P., Kuwata, T., Maruta, Y, Tanaka, K., Muntasir, A., Yoshimura, K., Matsushita, S.
  • Organizer: 15th Kumamoto AIDS Seminar
  • Place of Presentation: グランヴィリオホテル（阿蘇市）
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] Mutations in gp41 that confer resistance to fusion inhibitors enhance the neutralization sensitivity to antibodies against both gp41 and gp120. (2014)
  • Author(s): Muntasir, A., Kuwata, T., Ramirez, K., Enomoto, I., Maruta, Y., Tanaka, K., Rahman, K., Nakahara, Y., Egami, Y., Kawanami, Y., Murayama, H., Shimura, K., Matsuoka, M., Matsushita, S.
  • Organizer: 15th Kumamoto AIDS Seminar
  • Place of Presentation: グランヴィリオホテル（阿蘇市）
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] Mechanism of post-attachment neutralization of single-chain variable fragment (scFv) from anti-V3 monoclonal antibody against HIV-1. (2014)
  • Author(s): Maruta, Y., Kuwata, T., Tanaka, K., Nakahara,Y., Ramirez, K., Alam, M., Egami, Y., Hirata I., Suwa, Y., Morioka, H., Matsushita, S.
  • Organizer: 15th Kumamoto AIDS Seminar.
  • Place of Presentation: グランヴィリオホテル（阿蘇市）
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] Construction of neutralizing antibody fragment against V3 with a broad cross-reactivity. (2014)
  • Author(s): Tanaka K., Kuwata, T., Maruta, Y., Ramirez, K., Muntasir, A., Egami, Y., Enomoto, I., Kawanami, Y., Matsushita, S.
  • Organizer: 15th Kumamoto AIDS Seminar
  • Place of Presentation: グランヴィリオホテル（阿蘇市）
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] Passive transfer of neutralizing monoclonal antibody KD-247 reduces plasma viral load in patientschronically infected with HIV-1: a phase-1b clinical study of a humanized monoclonal antibody KD-247 (KD-1002). (2014)
  • Author(s): Matsushita, S., Yoshimura, K., Maeda, T, Murakami, T. KD-1002 Principal Investigators and The Protocol Team of Quintiles.
  • Organizer: 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention
  • Place of Presentation: Kuala Lumpur Convention Centre (Kuala Lumpur, Malaysia)
  • Year and Date: 2014-06-30 – 2014-07-03
• [Presentation] Passive transfer of neutralizing monoclonal antibody KD-247 reduces plasma viral load in patients chronically infected with HIV-1：A Phase-1b clinical study of a humanized monoclonal antibody KD-247 (KD-1002) (2014)
  • Author(s): Matsushita, S.
  • Organizer: IAS Towards an HIV Cure Symposium
  • Place of Presentation: The Banquet Hall, Rits Carlton Hotel(Kuala Lumpur, Malaysia)
  • Year and Date: 2014-06-29 – 2014-06-30
• [Presentation] KD-1002 Principal Investigators and The Protocol Team of Quintiles. Passive transfer of neutralizing monoclonal antibody KD-247 reduces plasma viral load in patientschronically infected with HIV-1: a phase-1b clinical study of a humanized monoclonal antibody KD-247 (KD-1002). (2013)
  • Author(s): Matsushita S.
  • Organizer: 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention
  • Place of Presentation: Kuala Lumpur, Malaysia.
• [Presentation] Passive transfer of neutralizing monoclonal antibody KD-247 reduces plasma viral load in patients chronically infected with HIV-1：A Phase-1b clinical study of a humanized monoclonal antibody KD-247 (KD-1002). (2013)
  • Author(s): Matsushita S.
  • Organizer: IAS Towards an HIV Cure Symposium.
  • Place of Presentation: Kuala Lumpur, Malaysia.
• [Presentation] Analysis of Env regions important for binding and resistance to B404, a potent neutralizing antibody against SIV. (2013)
  • Author(s): Kuwata T.
  • Organizer: AIDS Vaccine 2013
  • Place of Presentation: Barcelona, Spain.
• [Presentation] Improving the brodality and potency of neutralizing anti-HIV-1 antibodies with a CD4 mimetic compound. (2013)
  • Author(s): Ramirez K.
  • Organizer: AIDS Vaccine 2013
  • Place of Presentation: Barcelona, Spain.
• [Presentation] Identification of the Env region responsible for the resistance to B404, a potent neutralizing antibody against SIV. (2013)
  • Author(s): Kuwata T.
  • Organizer: 14th Kumamoto AIDS Seminar.
  • Place of Presentation: Kumamoto
• [Presentation] Miniaturization of antibodies against CD4-induced epitope on gp120. (2013)
  • Author(s): Tanaka K.
  • Organizer: 14th Kumamoto AIDS Seminar.
  • Place of Presentation: Aso, Kumamoto
• [Presentation] Can antibodies contribute to controlling infection with transmitted/founder virus? (2013)
  • Author(s): Ramirez K.
  • Organizer: 14th Kumamoto AIDS Seminar
  • Place of Presentation: Aso, Kumamoto
• [Presentation] Post-attachment neutralization as a mechanism of efficient activities of scFv from anti-V3 monoclonal antibody. (2013)
  • Author(s): Maruta Y.
  • Organizer: 14th Kumamoto AIDS Seminar
  • Place of Presentation: Aso, Kumamoto
• [Presentation] Effects of Enfuvirtide resistant mutations on the sensitivity to neutralizing antibodies. (2013)
  • Author(s): Alam M.
  • Organizer: 14th Kumamoto AIDS Seminar
  • Place of Presentation: Aso, Kumamot
• [Presentation] EVG/COBI/FTC/TDF 第III 相臨床試験における腎機能に関連する安全性の評価（投与96 週時点）－アジア人についての層別集計結果を含む－. (2013)
  • Author(s): 松下修三
  • Organizer: 第27回日本エイズ学会学術集会・総会.
  • Place of Presentation: 熊本
• [Presentation] シンポジウム６-中和抗体と抗CCR5 阻害薬(Env). (2013)
  • Author(s): 桑田岳夫
  • Organizer: 第27回日本エイズ学会学術集会・総会.
  • Place of Presentation: 熊本
• [Presentation] Combination of anti-V3 antibodies as a possible strategy for controllingtransmitted/founder virus. (2013)
  • Author(s): Ramirez K.
  • Organizer: 第27回日本エイズ学会学術集会・総会.
  • Place of Presentation: 熊本
• [Presentation] 抗V3 抗体の小型化によるCD4 結合後のHIV-1 中和活性の増進. (2013)
  • Author(s): 丸田泰広
  • Organizer: 第27回日本エイズ学会学術集会・総会.
  • Place of Presentation: 熊本
• [Presentation] Enfuvirtide resistant mutation N43Dis associated with the enhancedneutralization by 10E8, a broadlyneutralizing antibody against gp41 MPER. (2013)
  • Author(s): Alam M.
  • Organizer: 第27回日本エイズ学会学術集会・総会
  • Place of Presentation: 熊本
• [Presentation] gp120のCD4-induced epitope に結合する中和抗体の小型化とその特性の検討. (2013)
  • Author(s): 田中和樹
  • Organizer: 第27回日本エイズ学会学術集会・総会.
  • Place of Presentation: 熊本
• [Presentation] In vitro induction of ten CD4 mimic small compounds, NBD-556 and its analogues, resistant variants using primary R5 HIV-1. (2012)
  • Author(s): Harada S.
  • Organizer: XIX International AIDS Conference (AIDS 2012)
  • Place of Presentation: Walter E. Washington Convention Center (WCC), 米国ワシントン市
• [Presentation] Construction and characterization of neutralizing antibody fragments for efficient access to V3 epitope. (2012)
  • Author(s): Maruta Y.
  • Organizer: AIDS Vaccine 2012
  • Place of Presentation: The Boston Convention & Exhibition Center, 米国ボストン市
• [Presentation] Conformational epitope inbolving V3 and V4 loops is a major tartget for antibody-mediated neutralization in SIV smH635-infected macaques. (2012)
  • Author(s): Kuwata T.
  • Organizer: 13th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • Place of Presentation: 阿蘇グランヴィリオホテル, 熊本県阿蘇市
• [Presentation] Single-chain variable fragment (scFv) of anti-V3 monoclonal antibody efficiently neutralizes HIV-1 in vitro. (2012)
  • Author(s): Maruta Y.
  • Organizer: 13th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • Place of Presentation: 阿蘇グランヴィリオホテル, 熊本県阿蘇市
• [Presentation] Analysis of antibodies to CD4-induced epitope on gp120. (2012)
  • Author(s): Tanaka K.
  • Organizer: 13th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • Place of Presentation: 阿蘇グランヴィリオホテル, 熊本県阿蘇市
• [Presentation] Cross subtype neutralizing activity of plasma antibodies from patients infected with HIV-1 CRF01_AE HIV-1. (2012)
  • Author(s): Sonoda T.
  • Organizer: 13th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • Place of Presentation: 阿蘇グランヴィリオホテル, 熊本県阿蘇市
• [Presentation] SIV感染サルから分離された中和抗体B404はV3,V4ループを含むEnv立体構造を認識する (2012)
  • Author(s): 桑田岳夫
  • Organizer: 第26回日本エイズ学会学術集会・総会
  • Place of Presentation: 慶應義塾大学日吉キャンパス,横浜市
• [Presentation] CRF01_AE HIV-1 感染症例IgGの交差中和 活性の解析. (2012)
  • Author(s): 園田貴丈
  • Organizer: 第26回日本エイズ学会学術集会・総会
  • Place of Presentation: 慶應義塾大学日吉キャンパス,横浜市
• [Presentation] gp120のCD4-induced epitopeに結合する中和抗体の解析 (2012)
  • Author(s): 田中和樹
  • Organizer: 第26回日本エイズ学会学術集会・総会
  • Place of Presentation: 慶應義塾大学日吉キャンパス,横浜市
• [Remarks] 熊本大学エイズ学研究センター松下プロジェクト研究室
  • URL: http://matsushita-lab.kumamoto-univ.jp