勤智研究院｜New Targets in Immune-Oncology 腫瘤免疫新靶點｜2018 第一期
Forty-Seven Biosciences are a Menlo Park, California biotechnology company founded in 2015 as an offshoot of research conducted in Irving Wiesmann』s lab at Stanford. The team at Forty-Seven are focused on targeting the systems that regulate macrophage function. Their lead candidate is ananti-CD47 antibody named Hu5F9-G4 and is currently in Phase I clinical development for patients with advanced solid tumors and both Merck and Genentech have signed on with co-development agreements. Their work is novel and is aimed at a promising and mostly untapped field within immune-oncology.
To date Forty-Seven have raised 150M USD in two rounds of funding.Investors include Wellington Management, Lightspeed Venture Partners and Clarus Capital. The company also received a 5M USD grant from the California Institute for Regenerative Medicine. Lead by CEO Mark McCamish the team have inked deals with large pharmaceutical companies to pursue combination therapies. Merck and Forty-Seven aim to test Hu5F9-G4 in combination with Merck』s PD-L1 antibody avelimumab and initiated Phase I safety and dose finding tests of Hu5F9-G4 in patients with solid tumors and lymphoma. Results of the 96 patient trial have not yet been posted. Forty-Seven are also collaborating with Roche to test Hu5F9-G4 in combination with Rituximab in a Phase 1b/2 safety and efficacy trial in patients with relapsed or refractory B-cell lymphoma. Another deal with Roche was announced in early January to test Hu5F9-G4 in combination with subsidiary Genentech』s anti-PD-L1 antibody Tecentriq in patients with acute myeloid leukemia (AML) and bladdercancer.
Forty-Seven are not the only player with a CD47 asset. Celgene, Alexo Therapeutics and Trillium are competing in the space. Celgene is testingits CD47 antibody in Phase I trials in several indications including non-Hodgkin lymphoma, acute myeloid leukemia and myelodysplastic syndrome. Alexo have an asset ALX148 in Phase I trials in patients with solid tumors.Trillium are taking a somewhat different approach with an anti-body like molecule that inhibits CD47 function.They have two lead assets. One is under investigation in two clinical trials another is in late preclinical testing. The field is likely to be competitive but Forty-Seven are helped by their deals with large pharma and the scientific expertise of Dr. Weissman.
In brief, macrophages are cells of the innate immune system with acomplex role in tumorigenesis. Both pro-cancer and anti-cancer functions have been reported. Pro-growth functions including increased blood vessel formation,microenvironment remodeling and growth-factor secretion have been attributed totumor associated macrophages (TAMs). By contrast classical macrophages are likely to play ananti-cancer role by engulfing tumor cells in a process called phagocytosis. Macrophage phagocytosis is blocked when the CD47-SIRPα pathway is activated. SIPRα is expressed in macrophages. CD47 isexpressed on target cells. CD47 functions as a suppressor of phagocytosis – a『don』t eat me』 signal that suppresses engulfment. Expression of CD47 on healthy cells protects from aberrant phagocytosis to prevent an excessive immune response. Expression on cancer cells aids in escape from immune detection. The antibody under development at Forty-Seven Bio suppresses this protective 『don』teat me』 signal by blocking CD47 function. Conceptually its mechanism of actionis similar to the checkpoint inhibitors such as ipilimumab that target T-cells.By reversing a block to immune-mediated cell destruction, the antibody harnesses patients』 own immune system to fight cancer.
47生物科學（Forty-Seven Biosciences）是位於加州門洛帕克市的一家生物科技公司，成立於2015年，前身是斯坦福大學歐文?韋斯曼實驗室（Irving Wiesmann』s lab）的一個分支機構。47生物科學專註於研究靶向性調節巨噬細胞功能的系統。他們目前主要的研究成果是一個命名為Hu5F9-G4的anti-CD47抗體，該抗體目前正在對晚期實體腫瘤患者進行臨床一期，同時已經與默克（Merck）和基因泰克（Genentech』s）兩家公司簽署了共同開發協議。
目前47生物科學已經進行了兩輪總計1.5億美金的融資。投資者包括威靈頓資管（Wellington Management）, 光速創投（Lightspeed Venture Partners ）以及利思資本（ClarusCapital）。他們也收到了來自加州再生醫學研究所（California Institute for Regenerative Medicine）的500萬美金資助。由首席執行官馬克-麥卡米什（Mark McCamish）領導的團隊已經與大型製藥公司簽署了協議, 尋求組合療法。默克和47生物科學合作主要集中在測試 Hu5F9-G4 結合默克的 PD-L1 抗體葯 avelimumab 的效果以及啟動Hu5F9-G4 在實體腫瘤和淋巴瘤患者身上的Phase I安全性和劑量測試。目前96例患者的試驗結果尚未公布。羅氏和47生物科學的合作主要是測試Hu5F9-G4與Rituximab聯合使用在Phase 1b/2中對於複發性或疑難性 B 細胞淋巴瘤患者的安全性和療效。此外，2018年1月初，47生物科學與羅氏的子公司基因泰克也開展了一項合作，對急性髓系白血病 (AML) 與膀胱癌患者展開Hu5F9-G4與 anti-PD-L1抗體Tecentriq的聯合用藥測試。
47生物科學並不是唯一一個在關注CD47的玩家。賽爾基因（Celgene）, 埃里克斯葯業（AlexoTherapeutics）以及 延年健康（Trillium）都已經涉足這一領域。賽爾基因（Celgene）已經在展開CD47對於非霍奇金淋巴瘤、急性髓系白血病和骨髓增生異常綜合征等多個適應症的臨床一期測試。埃里克斯葯業（Alexo Therapeutics）的ALX148在用於實體腫瘤病人方面也已經進入臨床一期階段。延年健康（Trillium）另闢蹊徑的使用了一種帶有抑制CD47功能的抗體樣分子, 他們其中一個項目正在進行兩組單獨的臨床測試，而另外一個項目處於臨床前開發的後期。雖然這個領域已然是群雄逐鹿，但47生物科學身後的大藥廠和歐文?韋斯曼實驗室的科學家資源為這家公司提供了很好的幫助。
小結：巨噬細胞是先天免疫系統中對腫瘤發生有著複雜作用的一類細胞，其促癌和抗癌方面的功能均有報道。促癌方面表現為增加血管形成, 腫瘤微環境重構和生長因子的分泌, 都可歸因於腫瘤相關巨噬細胞（TAMs）的作用。相比之下, 經典巨噬細胞的吞噬功能可能會起到抗癌作用。通常情況下，當 CD47-SIRPα通路信號被激活時，巨噬細胞的吞噬作用會被阻斷。SIPRα表達於巨噬細胞表面， CD47表達於靶細胞。CD47 功能是通過釋放類似-「不要吃我」的信號, 從而抑制巨噬細胞的吞噬。CD47 在健康細胞上的表達可以保護細胞不受異常吞噬, 防止免疫反應過激，而CD47在腫瘤細胞上的表達則會幫助腫瘤細胞躲避免疫監測。47生物科技正在開發的一種特異性抗體會通過阻斷 CD47 的功能來抑制這種「不要吃我」的信號傳遞，從而促使巨噬細胞吞噬腫瘤細胞起到抗腫瘤功效。從概念上講, 其作用機制類似於免疫檢查點抑製劑（比如靶向 T 細胞的 ipilimumab 等），抗體通過逆轉阻斷免疫介導的細胞消亡的過程,利用患者自身的免疫系統來抗擊癌症。
作者：Stephen L.Mallon勤智資本高級投資經理
芝加哥大學放射腫瘤學博士後/微生物學博士
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