Tee Labs Incubatee: Full-Life Technologies – Conjugates Beyond ADCs, there Are Also RDCs
The co-founder of Full-Life Technologies told R&D-based Medicine, "The range of targets that can be developed for RDCs (Radiopharmaceutical-Drug Conjugates) is not very limited. In theory, RDCs can pursue any target that ADCs can, and they also have the advantage of a 'theranostic' approach."
Driven by the dual forces of pharmaceutical giants and capital, Radiopharmaceutical-Drug Conjugates (RDCs) are entering a period of accelerated development.
Over the past two years, domestic companies have been increasingly active in RDC product development. In December 2021, China Grand Pharma entered into a strategic partnership with Germany’s ITM, acquiring exclusive rights to three RDC diagnostic products in the Greater China region for a consideration of up to €520 million. From the end of last year to the present, several companies with RDC pipelines have completed a flurry of financing rounds: HTA Co., Ltd. secured a 320 million RMB Series D+ financing; Full-Life Technologies completed a $10 million seed round and a 250 million RMB Series A financing; and Ablaze Pharmaceuticals secured a $75 million Series A financing.
Globally, according to statistics from investment institutions, the field of targeted radiotherapy saw over 12 equity investment deals in 2021, with another 9 completed in the first eight months of 2022.
Theranostics for Cancer
In terms of drug structure, RDCs are similar to Antibody-Drug Conjugates (ADCs), still consisting of three parts: a ligand, a linker, and a payload. The slight difference is that the payload for RDCs is a radioisotope, and therefore, its linker must contain a specific functional group structure capable of carrying the isotope, known as a chelator.
Since 2016, the FDA has approved nine RDC drugs, seven of which are for cancer diagnosis and two for cancer therapy. The main indications involve prostate cancer and neuroendocrine tumors, with target focus on Prostate-Specific Membrane Antigen (PSMA) and Somatostatin Receptor (SSTR).
Based on approval data, the number of RDC diagnostic products significantly exceeds that of therapeutic products. To date, only two RDC therapeutic drugs have been approved for market—Lutetium (177Lu) oxodotreotide (Dotatate) and Pluvicto (177Lu-PSMA-617)—both of which belong to Novartis.
However, the current RDC pipeline landscape is showing a trend towards “theranostic pairs,” which involves using the same ligand to develop both diagnostic and therapeutic RDC products for a specific target. When the ligand is linked with radioisotopes like F-18 or Ga-68, it forms an imaging diagnostic product. When linked with isotopes like Lu-177 or Ac-225, it becomes a therapeutic product.
Leading international RDC development companies such as ITM, TELIX, and CLARITY have all adopted this strategy in their product pipelines (see ITM pipeline chart below).
“The unique theranostic pairing of RDCs can effectively construct a closed loop of tumor diagnosis, treatment, and efficacy assessment,” said Dr. Hanghai Ding, co-founder of Full-Life Technologies, citing the example of patients with late-stage prostate cancer. “One can first use Ga-68-PSMA for imaging diagnosis of the tumor. Then, based on the diagnostic results, PSMA-positive patients can be treated with Lu-177-PSMA to target and attack the tumor. After treatment, RDC imaging agents can be used again to assess the therapeutic effect.”
“Every step in this process is visualized and quantifiable. We can accurately know the number of mutated tumors in a patient’s body, which allows us to determine the dosage and also to quantitatively evaluate the treatment’s efficacy. This is something that companion diagnostic products like genetic testing cannot achieve,” said Dr. Hanghai Ding.
Theranostic pairing can also be used to enhance the safety of RDCs. While RDCs also face off-target issues during use, Dr. Ding explained that due to the nature of RDCs, their off-target quantity, the distribution of the radioisotope after off-target release, and its metabolic profile in the body can all be traced and quantified.
Furthermore, since most radioisotopes can exert their therapeutic effect from outside the cell, the conjugate does not need to be cleaved for the RDC drug to be effective. This improves its in-vivo stability and safety. It also allows the drug to not only target mutated cells but also to exert a killing effect on heterogeneous, non-mutated cells within the tumor (the cross-fire effect).
Seeking Product Differentiation
RDCs offer numerous advantages in precision oncology, but they are still a nascent field in China, with only a handful of RDC products from companies like China Grand Pharma and Novartis having submitted clinical trial applications. Notably, several domestic biotech startups have entered this field in the last two years, demonstrating a late-mover advantage.
Full-Life Technologies, where Dr. Hanghai Ding is a part of, was founded in August 2021. In just one year, the company has already advanced two products into the preclinical research stage and anticipates initiating first-in-human studies in Europe and the US in the third or fourth quarter of next year.
The three co-founders of Full-Life Technologies—Dr. Hanghai Ding, Dr. Zhong-Lian Huang, and Mr. David Sun—have accumulated experience in RDC diagnostic product development and biotech company management, giving them a unique advantage in developing RDC therapeutic products and producing radioisotopes.
Before founding Full-Life Technologies, Dr. Hanghai Ding and Dr. Zhong-Lian Huang were involved in RDC diagnostic product development at NanoMab Technology, where Dr. Ding was also a co-founder. NanoMab has two products that have advanced to the clinical research stage: NM-01, a Technetium-labeled anti-PD-L1 single-domain antibody, and NM-02, a Technetium-labeled HER2 single-domain antibody.
NM-01 is the world’s first PD-L1 imaging RDC drug approved to enter clinical trials and is currently in Phase II clinical studies. The product was licensed to the American imaging company Lantheus Medical Imaging in June 2019. Apart from this, all other products from NanoMab were also out-licensed last year.
According to Dr. Hanghai Ding, in RDC drug development, the design of the ligand and the chelator are core to the product’s technology, and these two elements are common to both RDC therapeutic and diagnostic products. The extensive experience in ligand and chelator development accumulated during their R&D at NanoMab could therefore be seamlessly transferred to Full-Life Technologies.
Another co-founder of Full-Life Technologies, Mr. David Sun, previously served as a Partner and Chief Investment Officer at the global life sciences venture capital firm Gordian Ventures. He was also a co-founder of the AI drug design company Silicon Therapeutics. In April 2021, Silicon Therapeutics was acquired by Roivant in a deal totaling $2.05 billion.
According to information published on the Full-Life Technologies website, the company has established a product pipeline targeting three targets: FAP, Claudin18.2, and GCC. Data shows that FAP is highly expressed in the microenvironment of various malignant solid tumors, and several companies have targeted it for RDC diagnostic product development. Claudin18.2 is primarily highly expressed in pancreatic and gastric cancers, while GCC is mainly highly expressed in colorectal cancer. These are currently all challenging tumors in clinical treatment.
Dr. Hanghai Ding believes, “The range of targets that can be developed for RDCs is not very limited. In theory, RDCs can pursue any target that ADCs can, and they also have the advantage of a ‘theranostic’ approach.”
Dr. Hanghai Ding also mentioned another innovation in Full-Life Technologies’ product development: attempting to use the same ligand conjugated with different radioisotopes to develop multiple products. For example, the FAP ligand could be conjugated with either Lu-177 or Ac-225 to suit different cancer treatment scenarios.
“Lu-177 produces beta (β) particles, which have stronger penetration but relatively weaker killing power, while Ac-225 produces alpha (α) particles, which have weaker penetration but much stronger killing power,” Dr. Ding explained. “We can select the isotope based on the patient’s stage and tumor size. Beta radiation can penetrate larger tumors, while alpha radiation can be used to target widespread micrometastases without causing excessive damage to surrounding healthy tissue. Depending on the need, we can also use a combination of different isotope-conjugated therapies for patients, potentially achieving better therapeutic outcomes.”
Addressing Supply Chain Pain Points
In addition to developing RDC therapeutic drugs, Full-Life Technologies also plans to build accelerator facilities in Belgium to independently produce Alpha and Beta therapeutic radioisotopes. This is another key differentiator for Full-Life Technologies compared to other RDC development companies.
The upstream RDC industry supply chain mainly involves three components: ligands, conjugates, and medical isotopes. The production of medical isotopes is a key bottleneck for the development of nuclear medicine in China at present, as most radioisotopes used in domestic clinical practice rely on foreign imports. To address this, in May 2021, several national ministries jointly issued the “Medium and Long-Term Development Plan for Medical Isotopes” to promote the research, development, and production of medical isotope products.
“Medical isotopes typically have short half-lives. For example, the half-life of Lu-177 is 6.7 days, and for Ac-225, it’s 9.9 days. Without dedicated facilities for the scheduled production of medical isotopes, patients cannot receive their treatment products in a timely manner,” Dr. Hanghai Ding mentioned. “Full-Life Technologies intends to build its own production facilities to ensure the supply of nuclides during large-scale clinical phases, thereby ensuring the smooth progress of clinical development and commercialization. This is a major advantage and key highlight for Full-Life compared to many global nuclear medicine development companies.”
The products Full-Life Technologies plans to develop primarily involve two isotopes: Lu-177 and Ac-225. Since the production of Lu-177 requires building a reactor and the international supply of Lu-177 is relatively sufficient, Full-Life Technologies has chosen to procure it from suppliers. Ac-225, however, will be produced by its own custom-built accelerator.
Previously, the China Nuclear Technology Network had introduced Ac-225, calling it “the world’s rarest drug.” The article mentioned that the current global annual production of Ac-225 is only enough to treat a few dozen patients.
Dr. Hanghai Ding stated that Full-Life Technologies has already secured appropriate talent for the construction and operation of isotope production facilities. “Members of the Full-Life production team have previously been involved in the production of various medical isotopes, including small-scale production of Ac-225. They have a deep understanding of accelerator operation, target design, cooling systems, and isotope separation technology.”
Full-Life’s choice to build its accelerator and radiopharmacy facilities in Belgium is due to the country’s extensive experience with experts in accelerator-based isotope production and international transport of radiopharmaceuticals. This is also because Europe has a long history and deep experience in the development and application of nuclear medicine. As Full-Life’s primary clinical sites and markets for its short- to mid-term drug development are in Europe and the US, the Belgian facility will provide crucial support.
Full-Life Technologies estimates that the final investment in the GMP facility project will exceed $100 million. The company plans for it to be constructed and operational in about three years.
“By the time the accelerator is officially operational, Full-Life Technologies expects to have 3-4 products in the clinical research phase, with more early-stage products in the pipeline,” said Dr. Hanghai Ding. In his view, a three-year timeline is sufficient for Full-Life Technologies to complete its transformation. He once took six years from the founding to the successful exit of NanoMab, but this time, with Full-Life Technologies, he is ready to make a bigger move in the nuclear medicine space. He is also very much looking forward to collaborating with domestic and international pharmaceutical companies to conduct clinical research on a global scale.