[Licensing Story_PharmAbcine] Development of single- or bi- specific anti-angiogenic antibody and technology transfer 11.07.2016

Development of single- or bi- specific anti-angiogenic antibody and technology transfer


With a motto to develop first-in-class and best-in-class human monoclonal antibodies (mAbs), PharmAbcine was established in October 2008 by a team of researchers who worked for the Korea Research Institute of Bioscience and Biotechnology belonging to the Korean government when they became the first winner of GATE (Get Armed to Explore Global Market) Project funded by Novartis in collaboration with the Korea Health Industry Development Institute and Korea Trade-Investment Promotion Agency.


PharmAbcine is now conducting Phase II clinical trials for tanibirumab, a fully human anti-angiogenic mAb against vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2/KDR), in Australia. Developed in 2008 for clinical application, tanibirumab can neutralize the biological activities of VEGFR2. As a result, it can block angiogenesis and inhibit tumor growth and metastasis. VEGF/KDR signaling is shown to be a key regulator for tumor angiogenesis. A number of products are being commercialized and studied in clinical studies. In addition to a chemically synthesized drug Sutent (sunitinib), representative mABs and/or protein drugs include Avastin (bevacizumab), Lucentis (ranibizumab), Eylea (aflibercept), and Cyramza (ramucirumab). These drugs are being used to treat tumors and eye diseases. Of these, Cyramza was approved in 2014 as treatment for metastatic stomach cancer. It has the same mechanism as tanibirumab by targeting VEGFR2.


In 2011, a Phase I trial was started to assess the safety and pharmacokinetics of tanibirumab in 26 Korean patients with advanced or metastatic cancer while Cyramza was already under Phase II and III trials for regulatory approval. Tanibirumab showed potent anti-angiogenic efficacy as well as anti-tumor activity against various cancer-involved experiments. Due to its unique cross-species reactivity in murine model, translational research is available, a unique feature of anti-VEGFR-2 mAbs. These characteristics have enabled PharmAbcine to make proper designs for target diseases in subsequent clinical trials, which gives reasonable promise of obtaining successful therapeutics with less clinical cost.


Prior to the approval of Cyramza, Imclone Systems Inc. had started to develop another mAb called IMC-1C11 and completed its Phase I trial with satisfactory results. The company also succeeded in developing CDP-791, a pegylated VEGFR2-neutralizing diFab antibody, in collaboration with UCB Pharma in Belgium. Although Imclone finished Phase I trials for both mAbs, they did not continue to conduct further clinical trials for both antibodies due to uncertain prospect for market authorization of Cyramza, let alone their burden to return newly developed antibodies to the original developer. Accordingly, this is the reason why PharmAbcine was eager to develop a first-in-class antibody such as tanibirumab at its initial stage. 

Beyond our expectation, Cyramza was approved by the U.S. Food and Drug Administration in 2014 as a single agent or concomitant therapy for treating advanced gastric or other cancer types after PharmAbcine finished its Phase I trial for tanibirumab in November 2013. Inevitably, PharmAbcine had to change its original target diseases for tanibirumab based on efficacy in animal models. In preclinical studies, tanibirumab had demonstrated anti-angiogenic efficacy against several cancer types including glioblastoma with cross-species reactivity. The current Phase II clinical trial for glioblastoma was based on the efficacy results of animal experiments.


Figure 1. Mode of Action of Tanibirumab


Under the circumstance that Cyramza outpaced tanibirumab in terms of development phase and the safety profile of tanibirumab is yet to be established in clinical trials, technology transfer of tanibirumab is a daunting job for PharmAbcine. Since the safety and pharmacokinetics of tanibirumab have been fully proven in Phase I trial, two technology transfers have been successfully made available under exclusive license agreements at home and abroad. For the domestic firm, their licensing-in purpose for tanibirumab was to apply it in the treatment of eye diseases such as senile macular degeneration using the anti-angiogenic antibody. Another licensee is 3SBio, a China-based biotechnology company. It entered into an exclusive licensing agreement with PharmAbcine for the development of tanibirumab for treating gastric cancer in China and other Asian countries. The two companies have continued to seek opportunities to expand their biologics pipelines.


In addition to VEGF, various factors (e.g., PlGF, angiopoetin, PDGF, HGF, FGF, and VE-cadherin) have been demonstrated to be major contributors to angiogenesis, increasing the number of capillaries in a given network. In general, clinical experience indicates that targeting VEGF-A alone produces significant anti-tumor response at the initial stage. However, repeated doses may ultimately cause cancer cells to develop drug resistance as demonstrated in Avastin. In this case, angiogenesis in various cancers may be mediated through interactions with other factors such as FGF and VEGF-A. In order to overcome the resistance problem of Avastin and improve anti-angiogenic properties, PharmAbcine developed a fully human bi-specific IgG antibody that may block VEGF/KDR and angiopoietin/TIE2 (endothelial-specific receptor tyrosine kinase 2) signaling simultaneously. With similar mechanism targeting VEGF, angiopoietin-2 is shown to be a key regulator in activation, migration, and sprouting angiogenesis. Currently, Amgen and Regeneron have endeavored to develop anti-tumor agents or ophthalmic agents that can bind and neutralize angiopoietin-2. Recent data from tumors have revealed that angiopoietin-1 is also involved in the final stage of vessel stabilization or maturation in angiogenesis via pericyte recruitment. Angiopoietin can promote angiogenesis by binding to TIE2. Its activity is optimal in the presence of multimer. 


Figure 2. Shematic Diagam of PMC-001


PMC-001 is a bi-specific IgG antibody that binds to VEGFR2/KDR and TIE2 simultaneously. It blocks angiogenesis. It inhibits tumor growth, metastasis, and/or resistance more significantly than single antibody treatment. Furthermore, the bi-specific feature of PMC-001 is advantageous in that development cost can be significantly reduced by formulating two substances into one compared to the cost used to independently develop two substances. This is self-evident in formulating existing medicines, although there exist some limitations such as proper maintenance of physical properties and dose adjustments on two signal systems. 


In preclinical studies, the superiority of PMC-001 over existing drugs was demonstrated in Avastin-resistant murine models of glioblastoma, pancreatic cancer, triple negative breast cancer, and other unmet medical needs. In particular, the efficacy of PMC-001 in animal models of pancreatic cancer paved the way to successfully make the technology transfer of PMC-001 in 2014. At that time, Phase I trial for PharmAbcine’s flagship antibody tanibirumab was completed with good safety and efficacy profiles.


In October 2014, PharmAbcine concluded a new global licensing deal with Triphase, a Canadian company, for PMC-001. Triphase was established under investment from Celgene. The keen interest of Celgene is focused on finding substance to boost the effectiveness of its blockbuster Abraxane (treatment for late-stage pancreatic cancer). We believe that Celgene’s earnest desire and preclinical proof-of-concept of PMC-001 both in in vitro binding assays and in in vivo efficacy in animal models of pancreatic cancer might lead to a successful technology transfer. Thereafter, PharmAbcine entered into another licensing deal with 3SBio for PMC-001 in addition to tanibirumab. 


In the process of technology transfer for PMC-001, we had to face some difficulty in supplying cell lines to two foreign companies. Both Triphase and 3SBio were desirous of using the same cell line as ours. However, the patent holder of the cell lines that permitted PharmAbcine to use them refused to allow 3SBio to employ their cell lines. This unexpected situation prompted us to produce alternative cell lines that would be free from the patent scope, thus causing prolonged delay for the whole development period. In this context, it can be safely said that base patent search of a platform technology such as cell lines should be performed in advance, although sophisticated and up-to-date technology is very important.


In addition to anti-angiogenic antibodies such as tanibirumab and PMC-001, PharmAbcine has devoted itself to the development of immune checkpoint antibodies and various concurrent dual receptor inhibitors in the field of oncology.