三优生物郎国竣:超万亿抗体库构建新里程 挑战难成药靶点

近日,三优生物正式发布了其具有自主产权的三优超万亿创新抗体药发现平台(STAL)。该平台由三优生物历时7年持续创新、自主研发而成,是在三优生物超千亿创新抗体发现平台的基础上取得的重大突破。

写意君采访了三优生物创始人兼CEO郎国竣博士,深入了解这个平台背后的故事。

郎国竣:三优生物创始人兼CEO

1、7年建起的抗体“海”

2015年,郎国竣创立三优生物,用他自己的话来说,那是“顺理成章”的事情。

彼时的他,已在复星医药旗下抗体药公司复宏汉霖工作多年,2012年左右小试牛刀地建成一个10的10次方级别(百亿级)抗体库,也带领创新研发和质量控制生物部团队参与了大约10个药物的研发。到他离开时,近一半药物报了IND,还有部分进入了临床。如今,这些药物有4、5个已上市。

后来他又到另一个公司做了一段时间的产品和营销负责人。“我觉得可以出来做点事了。”一方面,他想着可以把掌握的技术进一步完善、发展,做一个能服务更多药企的平台,从而有机会造福更多的患者;另一方面,他怀揣着“做一个能创造卓越价值的公司”的愿望,为了实现这个愿望,他决定创业。

“当时圈子里有很多老朋友的公司有创新方面的需求,加上我们的团队有营销的经验,我们比较确定我们可以养活自己。”掌握着技术、有订单来源,还有人愿意加入——郎国竣叫上两个朋友,组成了最早的三优生物团队。

第一年3个人,第二年10个,第三年27个,第四年50……他能清晰地数出三优生物成长的每一步。

就像他同样清晰地介绍着三优生物的LOGO。“它首先是像抗体。”郎国竣解释,“每个抗体上小小的叶子一样的元件则是小药片。这个元件和传统的抗体有点不一样,代表了我们想要创新。”LOGO就是由三个不同颜色的“创新抗体”组成——这个“三”即是“三优”的“三”,也是“三生万物”的“三”。

三个“抗体”下面有个圈——“像海一样,因为做抗体需要有很大的库,而抗体就是从这个海一般的库中长出来。”

三个“抗体”还像三个举着手的人。“这代表我们希望敞开胸怀、面向世界,与大家携手前进。”他从三优生物的LOGO开始将企业的愿景娓娓道来,“我们希望做到品质最好、速度最快、性价比最高,这是三优的核心理念。”

正如郎国竣设想的那样,三优生物一步步将能“生长”出抗体的“海”建了起来。

2015到2016年的阶段,三优生物能对外服务的是百亿级的抗体库以及中国市场上的首个小鼠免疫库。那时候,三优生物建起拥有自主产权的噬菌体展示载体系统,并完成了合成和半合成抗体库的设计。

到了2018年,三优生物发布首个千亿级人源抗体库,还有单域天然库、免疫库等,可以提供人源、鼠源、羊驼抗体的全面解决方案——这三种类型的抗体涵盖当时抗体药研发几乎所有品种。

2019年年初,三优生物启动了万亿抗体库的构建计划。而第一个真正建成的万亿级抗体库是在2020年12月,但三优生物规划中的不仅是一个万亿级抗体库,而是一系列。

“现在我们有5个万亿级的抗体库,共7万亿的超大库容。”历经7年时间,先后经过三代,三优的抗体“海”已经积累到全球占有绝对优势的量级。

但这还不是全部。

三优生物实验室

2、超万亿库+高通量筛选 高效发现先导分子

三优生物目前已建成的5个万亿级抗体库,分别是万亿全人重组抗体库、万亿人半合成抗体库、万亿人2C型单域抗体库、万亿人4C型单域抗体库、万亿人共同轻链单抗库。

这些库各有特点。如全人重组抗体库是全人B细胞基因克隆后的重组抗体库,源自天然,成药性好;全人半合成抗体库同样源自天然,再辅以工程设计,多样性好;两个单域抗体库抗体骨架的人源化程度达到98%,不需要再做人源化;共同轻链单体库特别适合用于发现双特异抗体……

合起来,这些库组可以实现全人抗体、单域抗体、双特异抗体、鼠单抗等分子形式全覆盖。

“这些抗体库从原始的技术积累开始,经过概念设计、建库,一点点建起来。”在三优生物的设计中,还有4个万亿级库正在建设中,包括万亿AC小型化蛋白库、万亿AF小型化蛋白库、万亿功能蛋白融合抗体库和万亿环状多肽库。9个超万亿级库的库容,合计高达10万亿。

如此大体量的抗体库,筛选是个难题,为了便于筛选,三优生物将“噬菌体展示抗体库与哺乳动物细胞蛋白表达”无缝衔接,打造自动化、高通量、精细化的一站式筛选平台。经过三年的打磨,三优生物建立自动化的生产体系,实现了高效率的筛选。

噬菌体展示是抗体产生的三大主流技术之一,该技术获得了2018年诺贝尔化学奖。噬菌体展示已经过10多个上市抗体药物验证,包括年销售规模突破200亿美元的“药王”阿达木单抗、被称为“最好银屑病新药”特诺雅单抗。

目前,全球噬菌体展示技术的代表企业包括剑桥抗体技术公司(CAT),其在2006年时,被阿斯利康收购了;另一个是德纳维制药(Dyax),该公司也于2015年被英国制药巨头Shire收购;尚未被制药企业收购的Morphosys是纳斯达克上市公司,前面提到的特诺雅单抗就是Morphosys与强生合作研发的,该公司已转型为生物技术公司。

与另一个主流技术杂交瘤相比,噬菌体展示的能量高,库容可以做到特别大。杂交瘤的小鼠免疫抗体库做到10的6次方(百万级)就到顶了,而噬菌体展示的可以做到10的10至11次方,例如CAT和Dyax的库容是10的10次方级别(百亿级),Morphosys的是10的11次方级别(千亿级),而三优生物更是做到了7×10的12次方级别(超万亿级)。

除了库容超大,筛选速度还特别快。杂交瘤技术很难做细胞筛选,比如百亿级的抗体,要用1万块板才能把抗体筛选完。“这基本上是不可能实现的事情。”他指出。而噬菌体展示技术是把细胞铺在板子上,让噬菌体展示流过去,洗掉脱落的、结合下来的就是所要的抗体。“只需要一块板或者一个管子就能解决,所以特别适合做拿不到抗原的细胞水平筛选。”基于此,杂交瘤需要5至6个月的筛选,噬菌体展示只需要5至6周就可以完成,而三优做过最快的,甚至只有16天。

那是2020年做的用于治疗新冠的抗体,从一个靶点抗原蛋白到把真核表达的抗体药物先导分子做出来只用了16天,“后来这个抗体转给了复宏汉霖。”当年10月,这个单抗获得了FDA的IND。

超大容量的抗体库、高效率的高通道筛选,可以快速地获得大量分子。“几个库加起来能获得2000个以上的先导分子,这个数量非常的优势,可以获得更高的成功率。”郎国竣很是自信。

3、高表达+高纯度+高亲和=高可开发性

能获得成药性更好的分子,对客户来说意义重大。噬菌体展示技术在这方面也有其独特的优点。

杂交瘤的小鼠免疫由于小鼠有很多抗原,免疫后往往只有一些抗原性强的抗原或者抗原表位可以持续地刺激小鼠产生抗体,其他抗原性不强的抗原或抗原表位难以产生抗体。这导致部分抗原免疫效果差、覆盖的表位优先,不能产生较好的功能分子,或者产生的功能分子的机制不够多样。

而噬菌体展示由于是体外技术,可以让抗体均匀覆盖各个表位,实现表位的全覆盖。因此,上述杂交瘤不能解决的问题,噬菌体展示都能较好的解决。

“再加上我们库的设计都是基于天然抗体的氨基酸分布规律,源于自然、接近天然,成药性和可开发性都很好。”郎国竣表示。

三优生物曾经对超万亿抗体库筛选出来的600多个抗体进行了统计,数据显示其中50%的单抗瞬转表达量在100㎍/mL以上,75%的纳米抗体表达量在300㎍/mL以上,抗体的表达水平高;61%的抗体亲和力都能达到10-9M以上,其中14%在10-10M以上,能符合做药的要求。

三优生物也曾经对超万亿抗体库筛选出来的1982个抗体进行SEC数据的统计,其中有1599个(占比81%)纯度超过90%,1441个(占比73%)纯度超过95%,证明从超万亿抗体库中筛选获得的抗体中符合做药要求的抗体的比例高。

除了前面提到了新冠抗体药,三优生物还做过一个新冠双抗药,和之江生物联合研发,并由勃林格殷格翰(BI)负责工艺优化及生产制造服务,虽然后来受到疫情和市场环境影响,推进变缓,但目前也完成了临床前研发,进行到中美pre-IND阶段,证明了该抗体药的可开发性。这是我国原创研发的抗新冠病毒治疗的抗体药物,也是全球研发进展较为领先的双特异性抗体药物。

新冠抗体药物相关的研究还和合作单位一起在Science、Cell research和Cell discovery等权威期刊上发了文章。

三优生物还和宝船生物合作开发了针对CLDN18.2的抗体。

CLDNs谱系的靶向治疗研究已得到广泛关注,尤其是靶向CLDN18.2药物在胃癌领域的应用。三优生物当时做正是靶向了CLDN18.2的抗体,“我们同时做了全长抗体和纳米抗体,其中纳米抗体比较领先。”

该抗体已获得了NMPA的临床试验默示许可,将开展用于CLDN18.2阳性晚期恶性消化道实体瘤治疗的临床试验。

三优生物还累积了几十个其他创新抗体药物早期发现的经验、数百个项目的阶段研发经验,这些经验和优势,让三优生物能承接更多的项目。“现在是上百个整体项目和数百个阶段项目在运转的过程中。”

4、创新药出海道路渐明

郎国竣介绍,三优生物已与300多家客户进行合作,基本上每个合作过的客户都会开展二次合作,部分客户的合作次数已经达到了10多次。未来,三优生物还会继续拓展客户,除了国内客户,还有国际客户——这部分也在跟进过程中,已有10多个签单。“我希望能为所有的制药公司、药物研发单位提供服务,助力他们的药物研发。”郎国竣表示这是三优生物的核心目标。

三优生物的业务涵盖了CRO、CPO和CRS三大部分:从靶点到PCC再到IND各阶段,从单抗、双抗、ADC偶联、CAR-T、基因治疗等各种技术的CRO服务;包括PCC和IND定向研发、合作预研、授权转让多种模式的CPO服务;以及蛋白、抗体、细胞和诊断试剂4大类的CRS核心试剂。

“我希望在这些基础上把一体化做得更好,将临床前的CDO整合进来。”他提到三优生物和白帆生物等CDMO单位的战略合作,和这些单位一起提供完整的临床前解决方案,他表示,“三优生物也正在建设中试基地。”

在创新方面,三优生物在积极布局各个治疗技术领域,如PDC、三抗等。

PDC即多肽偶联药物,“我们要建到万亿级的多肽库,筛选靶向型多肽分子,希望能突破胞内的靶点。”郎国竣设想,多肽和小分子药物偶联,利用多肽的靶向性进入胞内,在多肽上再连一个功能肽或小分子药物,可作用于胞内的靶点,“这是今年的重点方向,目前这个库的前期调研和设计已经完成,正在概念测试中,估计再花三个月就差不多可以上线了。”

同时,在肿瘤、自身免疫性疾病、代谢疾病等领域,也通过定向推荐的模式,由三优生物的科学家帮助客户做些调研立项的辅助工作,他希望通过这些动作解决一些高难度的靶点,从而满足一些临床未满足的疾病治疗需求。

比方说G蛋白偶联受体(GPCRs),其在糖尿病、肥胖症、AD以及心理疾病方面的重要作用,一直是热门明星靶点,已获得FDA批准的靶向GPCR的小分子药物达475种,占所有FDA批准药物的35%。然而,由于其具有7次跨膜、靶点结构不稳定、构象复杂、表达率低、蛋白难以制备等特点使得大分子药物开发难度巨大,是业界公认的“超高难度的靶点”。

“我们组建了专门的团队在攻克这类靶点。”他介绍,三优生物的超万亿创新抗体药物发现平台的种种优势,使其适用于这些高难度靶点的复杂筛选,而郎国竣也希望在这些方面有所突破。

类似于GPCR这类的专题创新在三优生物大概有10多个,“每个专题方向都布局了一个小团队在做。”无论是建更多类型的抗体库,从而筛选出更多类型的大分子,还是攻克更多高难度靶点,都是以不同的创新手段,为大分子创新药物的研发提供更多的可能性,为满足临床需求提供更多的解决方案,让最终的产品能更具差异化,突破抗体研发的内卷现状。

目前,从三优生物出来的抗体药物已有5个申报临床或已获得临床批准,“在未来10年,我希望能达到100个。”郎国竣期待着。

郎国竣博士介绍

郎国竣,浙江大学生物化学与分子生物学专业博士,拥有10余年创新抗体药研发及产业化经验。2015年领衔创立三优生物,担任董事长兼CEO至今。经过7年深耕,三优已发展为行业领先的创新抗体药研发服务公司,拥有以硕士博士为主的团队250多人,已为全球300多家制药和药物研发机构提供了药物研发服务。

创立三优生物前,郎国竣博士曾在复宏汉霖(复星医药成员)、Henlius(USA)等公司担任高级研究员、研发经理、质控经理、产品总监和BD副总裁等职位;曾获2013年上海市科技创新新人奖、2014年上海市科技英才候选人等荣誉。

郎国竣博士在抗体药研发、产业化和商业运营方面经验丰富。作为骨干或带团队参与研发的药物中有10多个已进入临床,多个药物已成功上市,另有数十个项目在临床前研发阶段;带领团队完成的超万亿抗体发现平台的核心技术参数居于国际领先水平;曾作为项目负责人或者研发骨干参与过10余项“国家及省级重大新药创制或攻关项目”;累计已申请发明专利58项,授权发明专利10余项;发表SCI论文15篇。

英文译文

Guojun Lang, CEO of Sanyou: New milestone in the establishment of super-trillion antibody libraries for antibody discovery of challenging targets

Recently, Sanyou Biopharmaceuticals officially launched its independently developed Super-Trillion Antibody Libraries (STAL), and the concomitant innovative antibody drug discovery platform. Established by Sanyou after seven years of continuous innovation and independent R&D, the STAL antibody drug discovery platform represents a significant breakthrough over the previous generation of the sub-trillion innovative antibody discovery platforms.

Xie Yijun interviewed Dr. Guojun Lang, the founder and CEO of Sanyou, to learn more about the story behind the platform.

A vast resource of antibodies built up in 7 years

In 2015, Dr. Lang founded Sanyou Biopharmaceuticals, which seemed to be spontaneous to him.

At that time, he had been working in Henlius, an affiliate to Fosun Pharma specialized in R&D of antibody drugs, for several years. Around 2012, he built an antibody library of 10^10 (10 billion) capacity and led the team of Innovative R&D Department and Biologics Quality Control Department to participate in the R&D of more than ten antibody drugs. By the time he left Henlius, nearly half of those drugs had been filed for IND, and some had entered the clinic trails. As of now, five of them have been launched onto the market.

Dr. Lang then worked for another company for a short period as the head of product and marketing. "I was thinking it was time to put my ideas into actions." The first idea is to further develop and improve the technologies he mastered, so as to establish a platform that serves more pharmaceutical enterprises and thus have the opportunity to benefit more patients; on the other side, he hoped "to establish a company that creates superior values for the society". In order to carry out these ideas, he decided to start his own business.

"There were a lot of requirements for drug innovation from companies of my friends in the community, and our team had marketing experiences. Therefore we were sure we could make ends meet." With the technology, contracts, and people willing to join, Dr. Lang, together with two friends, founded Sanyou Biopharmaceuticals.

“The team of three in the first year of establishment grew to 10 members in the second year, 27 in the third year, 50 in the fourth year.” He clearly counted the number of staffs in every step of Sanyou's development.

Likewise, he is very familiar with Sanyou's LOGO. "It's like antibodies," Dr. Lang explained, "The tiny leaf-like elements on each antibody are pills. Those elements are a bit different from traditional antibodies, which represents our desire to innovate." The LOGO consists of three "innovative antibodies" in three different colors. "Three" represents "San" in "Sanyou", and "San" is "three" in Chinese, According to traditional Chinese philosophy "Three produced all things".

There is a circle under the three "antibodies". "It's like a big pool, as big as the sea, which represents the library. This library can generate a wide variety of antibodies to meet the drug discovery requirements."

The three "antibodies" also look like three people with their hands up and holding. "This represents our desire to open our hearts to the world and advance hand in hand with everyone." He explained the vision of Sanyou starting with its LOGO, "We want to deliver with the best quality, highest speed and top cost-efficiency, which is the core philosophy of Sanyou."

As Dr. Lang envisaged, Sanyou Biopharmaceuticals has established three generations of distinct antibody libraries, from which dozens of antibody drug projects were delivered.

From 2015 to 2016, Sanyou provided CRO services with its 10-billion-level antibody libraries and the first mouse immunization library in the Chinese market. At that time, Sanyou had established its independently developed phage display vector system and completed the design of synthetic and semi-synthetic antibody libraries.

In 2018, Sanyou launched the first sub-trillion human antibody library, as well as the naive single-domain library and immunization library, which provide comprehensive solutions for human, mouse, and alpaca antibodies covering the R&D of almost all varieties of antibody drugs at that time.

At the beginning of 2019, Sanyou initiated its plan for the construction of trillion-level antibody libraries. The first trillion-level antibody library was actually completed in December 2020, but what Sanyou planned to establish was a series of trillion-level libraries, rather than only one trillion antibody library.

"Now we have five trillion-level antibody libraries, with a large library capacity of seven trillion in total." After 7 years of upgrading for three generations, the property and performance of Sanyou's super-trillion antibody libraries are showing international advantages.

There is still more.

Highly-efficient discovery of lead antibodies with super-trillion libraries and high-throughput screening

At present, Sanyou has completed 5 trillion-level antibody libraries, i.e., fully human recombinant antibody library, fully human semi-synthetic antibody library, humanized 2C/4C single domain antibody libraries, and fully human common light chain antibody library.

Each of these libraries has its own characteristics. For example, the fully human recombinant antibody library is designed by recombination of antibody nucleotides from human B cells, to maintain natural sequences and improve drug developability; the fully human semi-synthetic antibody library is also derived from natural sequences, supplemented by molecular engineering designs to enhance the diversity; the degree of humanness for the antibody framework of the two humanized single domain antibody libraries is as high as 98%, with no need for further humanization; the common light chain antibody library is particularly suitable for the generation of bi-specific antibodies.

These libraries together can achieve full coverage of the antibody formats, such as fully human antibody, single-domain antibody, bi-specific antibody and mouse monoclonal antibody.

"These antibody libraries have been gradually established from the accumulation of the background technologies, conceptual design, to library constructions step by step." There are also four trillion-level libraries under construction according to Sanyou's plan, including trillion-level AC miniaturized protein library, trillion-level AF miniaturized protein library, trillion-level functional protein fusion antibody library, and trillion-level cyclic polypeptide library. The capacity of the 9 super-trillion libraries will be more than 10 trillion in total.

Screening with such large antibody libraries is a challenge. In order to facilitate screening, Sanyou effectively integrated technologies of phage display antibody libraries and protein expression by mammalian cells, and established an automated, high-throughput, and refined one-stop screening platform. After three years of refining, Sanyou Biopharmaceuticals has established an automatic R&D system to achieve highly efficient screening.

Phage display technology is one of the three mainstream technologies for antibody generation which was awarded for the Nobel Prize in Chemistry in 2018. Phage display technology has been verified by more than 10 commercially launched antibody drugs, including adalimumab, the top-sales medicine with annual sales of more than $20 billion, and Tremfya, known as the "best new drug for psoriasis".

The current global representative enterprises of the phage display technology include Cambridge Antibody Technology (CAT), which was acquired by Astrazeneca in 2006; Dyax, which was acquired by Shire, an UK pharmaceutical giant, in 2015; Morphosys, a Nasdaq-listed company that has not been acquired by any pharmaceutical company, developed aforementioned Tremfya in partnership with JNJ, and has converted into a biotechnology company.

Compared to hybridoma, another mainstream technology, phage display library enables high throughput and extremely large capacity. The capacity of mouse immune antibody library for hybridomas is up to 10^6 (million), while that of the phage display can be 10^10 to 10^11. For example, CAT and Dyax have a library capacity of 10^10 (10 billion), Morphosys has a library capacity of 10^11 (sub-trillion), while Sanyou achieved 7×10^12 (trillion).

In addition to the large library capacity, screening speed is another advantage. It is difficult to screen cells with the hybridoma technique. For example, it takes 10,000 plates to screen ten billion antibodies. "It's not practical in the real labs," said Dr. Lang. With phage display, on the other hand, the cells are fixed on a plate, allowing the phages to flow through, non-binders to be washed away, and the binding antibodies to remain. "It only takes a plate or a tube to do that, so it's particularly suitable for screenings where you have to use cells instead of unavailable protein antigens." In comparison, the screening takes 5 to 6 months for hybridoma, while phage display takes only 5 to 6 weeks, or as short as 16 days according to the best record of Sanyou.

That antibody was developed in 2020 for the treatment of COVID-19, and it took us only 16 days from the antigen protein to the generation of the eukaryotic expressed lead antibody, which was later transferred to Henlius. In October of that year, that monoclonal antibody obtained IND approval by the FDA.

A large number of lead antibodies can be quickly obtained from the ultra-large antibody libraries and highly-efficient high-throughput screening. "More than 2,000 lead antibodies can be obtained from these libraries, which guarantees much higher success rate of the drug R&D," said Dr. Lang with confidence.

High expression + high purity + high affinity = high developability

Having access to lead antibodies that have better drug developability is of great significance to clients. Phage display technology also has its unique advantages in this respect.

For the mouse immunization of hybridoma, since mice have many antigens, only some antigens or epitopes with strong immunogenicity will continuously stimulate the mice to produce antibodies after immunization, while other antigens or epitopes with weak immunogenicity could rarely do that. This results in poor immune effect of some antigens, limited coverage of epitopes, lack of good functional candidate antibodies, or insufficient in the candidate functional diversity.

Phage display, as an in vitro technology, can generate antibodies to cover most of the epitopes. Therefore, phage display can overcome the above drawbacks of the hybridoma technology.

"In addition, our libraries are designed based on the amino acid distribution of natural antibodies, which is natural or similar to the natural sequences with good drug properties and developability," said Dr. Lang.

Sanyou had conducted statistical analysis on more than 600 antibodies screened from super-trillion antibody libraries. The data showed that the transient expression level of 50% monoclonal antibodies was over 100 μg/mL, and the expression level of 75% nanobodies was over 300 μg /mL, indicating high expression level of those antibodies; 61% of the antibodies had affinity higher than 10-9M, and 14% of them higher than 10-10M, meeting the requirements of drug screening.

Sanyou had also carried out statistics on the SEC results of 1,982 antibodies screened from the super-trillion antibody libraries, among which 1,599 antibodies (81%) had a purity of more than 90%, and 1,441 ones (73%) more than 95%, proving that high proportion of the antibodies from the super-trillion antibody libraries meet the purity requirements for antibody drugs.

In addition to the monoclonal antibody drug mentioned above, Sanyou also developed a bispecific antibody drug for COVID-19 in collaboration with Liferiver, and Boehringer Ingelheim (BI) was in charge of the process optimization and manufacturing services. Although the project was delayed later due to the pandemic and changing market environment, the pre-clinical research and development have been completed and the pre-IND filing was accomplished in China and the United States, which reflects the developability of the antibody drug. This is an antibody drug for COVID-19 treatment developed by the Sanyou R&D team, as well as an advanced bispecific antibody drug in this field.

Researches related to the above COVID-19 antibody drugs have also been published in prestigious journals such as Science, Cell Research, and Cell Discovery.

Sanyou also collaborated with Dragon Boat Biopharmaceutical to develop antibodies targeting CLDN18.2.

The study on targeted therapy of the claudin family has attracted extensive attention, especially the application of targeted CLDN18.2 drugs in the treatment of gastric cancer. Sanyou was developing antibodies targeting CLDN18.2 at that time. "We were developing full-length antibodies and nanobodies at the same time, and the latter was making greater progress."

This antibody drug has obtained the implied approval for clinical trials from NMPA, and will be studied in the clinical trials for the treatment of CLDN18.2-positive advanced malignant gastrointestinal solid tumors.

In addition, Sanyou has accumulated experiences in the early discovery of dozens of other innovative antibody drugs and in the staged R&D of hundreds of projects. These experiences and advantages prepared Sanyou for more projects. "Now we have more than one hundred integrated projects and hundreds of staged projects under development."

Time for the innovative drugs R&D services to go abroad

According to Dr. Lang, Sanyou has provided services to or cooperated with more than 400 clients, where almost every existing client would seek cooperation for the second time, and some of them have worked with Sanyou on more than 10 projects. Sanyou will continue to expand its domestic and oversea business. "I hope to provide services for all pharmaceutical companies and biotech enterprises and boost their drug R&D." Dr. Lang says this is the core goal of Sanyou.

The business scope of Sanyou covers CRO, CPO (cooperative project organization), and CRS (core reagent solutions). CRO services range from target validation to PCC and to IND, and include monoclonal antibody, bispecific antibody, ADC, CAR-T and gene therapy; CPO services include PCC and IND directional R&D, cooperative R&D, and license transfer; and four categories of CRS core reagents include proteins, antibodies, cells and diagnostic reagents.

"I want to improve our one-stop services by integrating pre-clinical CDO on top of our existing services. A plant for the pilot production is under construction." said Dr. Lang, referring to Sanyou's strategic partnerships with Dragon Sail Pharmaceutical and other CDMOs to provide the integral pre-clinical solutions.

In terms of innovation, Sanyou is actively setting foot in various fields of the therapeutic technologies, such as PDC, trispecific antibodies, etc.

PDC refers to polypeptide coupling drugs. "We are planning to build a trillion-level polypeptide library for screening affinitive polypeptides, and hoping to make breakthroughs for intracellular targets." Dr. Lang proposes that peptides and micromolecular drugs may be coupled to enter the cell by taking advantage of the targeting ability of the peptides, and act on intracellular targets. "This is what we will focus on this year. At present, the preliminary research and design of the library have been completed, and the conceptual test is under way. It is expected to be launched in three months.

"At the same time, in the fields of tumors, autoimmune diseases, metabolic diseases, etc., scientists at Sanyou also help clients with target research and project validation through directional recommendation. He hopes to solve the problems with some highly challenging targets through these actions, so as to meet some unsatisfied demands for clinical disease treatment.

For example, G-protein-coupled receptors (GPCR), which play a significant role in diabetes, obesity, AD, and mental illness, have always been popular targets. A total of 475 micromolecular drugs targeting GPCR have been approved by the FDA, accounting for 35% of all FDA approved drugs. However, as they are tricky proteins with 7 transmembrane domains, instable target structure, complex conformation, low expression level, difficulty for protein preparation, and other characteristics, the development of biological drugs for GPCR is extremely challenging, and they are recognized as "ultra-difficult targets" in the industry.

"We have specialized teams working on these targets." According to Dr. Lang, the advantages of Sanyou's STAL discovery platform make it feasible for the complex screening of these highly challenging targets, and he also hopes to make breakthroughs in these areas.

In Sanyou, there are more than 10 innovative directions similar to GPCR, and every direction has its own team in charge. The discovery of more types of antibody drugs in the aid of vast antibody libraries, and the delivery of more projects for highly challenging targets are different innovative means aiming to provide more possibilities for the R&D of innovative antibody drugs, offer more solutions to meet clinical needs, make differentiated final products, and avoid unnecessary resource consumptions.

At present, five antibody drugs originated from Sanyou have been filed for or approved for the IND. "I hope the number will exceed 100 in the next decade," said Dr. Lang with great expectations.

Guojun Lang, Ph.D. of Zhejiang University and majored in Biochemistry and Molecular Biology, has specialized in the R&D and industrialization of innovative antibody drugs for more than a decade. In 2015, he led the foundation of Sanyou Biopharmaceuticals, and has served as the chairman and CEO. After 7 years of persistent endeavor, Sanyou has become an industry-leading company comprised with a team of more than 250 members and most of them have master's or doctoral degrees. Sanyou has provided innovative antibody drug R&D services to more than 300 pharmaceutical companies and drug R&D institutes around the world.

Before founding Sanyou, Dr. Lang worked as senior scientist, R&D manager, QC manager, product director and vice president of BD at Henlius (Shanghai) (an affiliate of Fosun Pharma), Henlius (USA) and Abmart. He was granted the 2013 Shanghai Science and Technology Innovation New Talent Award, the 2014 Shanghai Science and Technology Elite Candidate, and other honors.

Dr. Lang is experienced in the R&D, industrialization and commercial operation of antibody drugs. Among the drug R&D projects where he serves as a core member or the team leader, over 10 drugs have entered the stage of clinical trials, and several drugs have been launched onto the market, followed by dozens of other drugs in the pre-clinical R&D stages. The super-trillion antibody discovery platform developed by the team he leads boasts internationally leading core technical parameters. He once served as the leader or core R&D member of more than 10 major Provincial or National Major Scientific and Technol.

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