從原始文獻看第一個PD1抗體臨床試驗科研團隊不同成員的貢獻
6 人贊了文章
很少有人知道第一個PD1抗體，神葯Opdivo, 學術名Nivolumab， 最早在醫學文獻裡面的名字是MDX-1106, MDX的命名來自幫助James Allison開發CTLA-4抗體的公司Medarex.
我前面曾經說過James Allison主導了CTLA-4抗體的研發，藉助的力量就是Medarex, 下面這篇諾獎獲獎者關鍵科學貢獻的文章裡面我標註了3個人。
Hodi, F.S., Mihm, M.C., Soiffer, R.J., Haluska, F.G., Butler, M., Seiden, M.V., Davis, T., Henry-Spires, R., MacRae, S., Willman, A., Padera, R., Jaklitsch, M.T., Shankar, S., Chen, T.C., Korman, A.,Allison, J.P. & Dranoff, G. (2003). Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients.Proc Natl Acad Sci USA,100(8), 4712-4717.
James Allison, Medarex公司負責CTLA-4抗體開發的Korman, 還有後來獨立領導PD-L1抗體研發的Hodi, CTLA-4人體臨床試驗的結果2003年完成發表， 顯然研發CTLA-4抗體的布局更早就開始了。
Medarex開發的CTLA-4抗體臨床試驗在2003年成功之後， 2005年， Medarex授權給日本小野製藥公司開發PD-1抗體MDX-1106. Medarex成功的開發了CTLA-4抗體之後，下面一個對象是什麼還用說嗎？而且日本的企業早就開始布局並投資美國的抗體生物葯業， 為什麼日本人會有這樣的戰略眼光， 我就不多說了， 知識分子專欄的文章說得更加清楚。所以就開發第一個PD-1抗體的商業計劃來說，關鍵人物其實是Medarex和小野製藥的決策者。
下面重點說說PD-1抗體的第一次臨床試驗， 這是約翰霍普金斯醫院的研究團隊主導進行的， 這一點沒有任何爭議。
看第一次的PD-1/MDX-1106臨床試驗, 如果上PubMed檢索MDX-1106, 有2624篇文章，最早的就是下面這一篇。
J Clin Oncol. 2010 Jul 1;28(19):3167-75. doi: 10.1200/JCO.2009.26.7609. Epub 2010 Jun 1.
Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates.
Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL, Gilson MM, Wang C, Selby M, Taube JM, Anders R, Chen L, Korman AJ, Pardoll DM, Lowy I, Topalian SL.
Author information
Abstract
PURPOSE:Programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, may suppress antitumor immunity. This phase I study sought to determine the safety and tolerability of anti-PD-1 blockade in patients with treatment-refractory solid tumors and to preliminarily assess antitumor activity, pharmacodynamics, and immunologic correlates.
PATIENTS AND METHODS:Thirty-nine patients with advanced metastatic melanoma, colorectal cancer (CRC), castrate-resistant prostate cancer, non-small-cell lung cancer (NSCLC), or renal cell carcinoma (RCC) received a single intravenous infusion of anti-PD-1 (MDX-1106) in dose-escalating six-patient cohorts at 0.3, 1, 3, or 10 mg/kg, followed by a 15-patient expansion cohort at 10 mg/kg. Patients with evidence of clinical benefit at 3 months were eligible for repeated therapy.RESULTS:Anti-PD-1 was well tolerated: one serious adverse event, inflammatory colitis, was observed in a patient with melanoma who received five doses at 1 mg/kg. One durable complete response (CRC) and two partial responses (PRs; melanoma, RCC) were seen. Two additional patients (melanoma, NSCLC) had significant lesional tumor regressions not meeting PR criteria. The serum half-life of anti-PD-1 was 12 to 20 days. However, pharmacodynamics indicated a sustained mean occupancy of > 70% of PD-1 molecules on circulating T cells > or = 2 months following infusion, regardless of dose. In nine patients examined, tumor cell surface B7-H1 expression appeared to correlate with the likelihood of response to treatment.CONCLUSION:
Blocking the PD-1 immune checkpoint with intermittent antibody dosing is well tolerated and associated with evidence of antitumor activity. Exploration of alternative dosing regimens and combinatorial therapies with vaccines, targeted therapies, and/or other checkpoint inhibitors is warranted.作者列表裡面我用黑體標註了幾位重要人物， 下面是文章末尾介紹的各位作者的貢獻。
AUTHOR CONTRIBUTIONS
Conception and design: Julie R. Brahmer, Drew M. Pardoll, Israel Lowy, Suzanne L. Topalian （臨床試驗的概念和設計）
Provision of study materials or patients: Julie R. Brahmer, Charles G. Drake, Ira Wollner, John D. Powderly, Joel Picus, William H. Sharfman, Changyu Wang, Mark Selby, Alan J. Korman, Israel Lowy （抗體和病人募集）
Collection and assembly of data: Julie R. Brahmer, Charles G. Drake, John D. Powderly, Elizabeth Stankevich, Alice Pons, Theresa M. Salay, Tracee L. McMiller, Changyu Wang, Janis M. Taube, Robert Anders, Alan J. Korman, Israel Lowy, Suzanne L. Topalian （收集數據）
Data analysis and interpretation: Julie R. Brahmer, Charles G. Drake, Joel Picus, Theresa M. Salay, Tracee L. McMiller, Marta M. Gilson, Changyu Wang, Janis M. Taube, Robert Anders, Lieping Chen, Alan J. Korman, Drew M. Pardoll, Israel Lowy, Suzanne L. Topalian （數據分析和解釋）
Manuscript writing: Julie R. Brahmer, Charles G. Drake, Drew M. Pardoll, Israel Lowy, Suzanne L. Topalian （文章寫作）
Final approval of manuscript: Julie R. Brahmer, Charles G. Drake, Ira Wollner, John D. Powderly, Joel Picus, William H. Sharfman, Elizabeth Stankevich, Alice Pons, Theresa M. Salay, Tracee L. McMiller, Marta M. Gilson, Changyu Wang, Mark Selby, Janis M. Taube, Robert Anders, Lieping Chen, Alan J. Korman, Drew M. Pardoll, Israel Lowy, Suzanne L. Topalian （文稿審核）
看到這裡，大家應該了解整個霍普金斯團隊各位成員對第一次PD1抗體臨床試驗的貢獻了， 誰是真正的領導者一目了然。
推薦閱讀：