i2 Pharmaceuticals at a glance
- Began operations as a Corporation in Boulder, Colorado, in Q3 2014
- Fully operational lab for both Chemical and Biological Research and Development (14,000+ sq. ft.)
- Building out GMP manufacturing for RNA therapeutics in 2017
- Acquired in vitro directed evolution (Parallel SELEX) patents, know how, technologies, product candidates, licenses and materials in 2014
Antibody and “Antibody Like” Compounds
- Acquired Sea Lane Biotechnologies patents, know how, technologies, product candidates, and materials in 2016
History of Monoclonal Antibody (mAb) Discovery Technologies
Monoclonal antibody therapeutics represent the fastest growing class of pharmaceutical products, and mAb based companion diagnostics have facilitated the success of targeted therapies across a wide range of diseases and conditions. From 1975, when Kohler and Millstein generated the first mouse (murine) mAbs using the hybridoma technique, it was clear they had many attractive properties for discovery and development of novel biopharmaceutical products. Monoclonal antibodies combine high affinity and specificity for their target (antigen), have innate effector functions which can be engineered to modulate how they interact with host immune systems, have long half-lives in patients so often have dosing convenience, and can be manufactured with a range of expression systems. Over 30 mAbs are currently approved by the FDA for use in humans treating among others, cancer, chronic inflammatory diseases, transplantation, infectious diseases and cardiovascular diseases. The global value of the therapeutic mAb market is over $20 Billion per year and growing.
If at First You Don’t Succeed . . .
The first approved mAb therapeutic was Orthoclone OKT3 (muromonab-CD3), approved in 1986 for use in preventing kidney transplant rejection. This is a mouse mAb, showing mouse mAbs could be safe and efficacious. However, such mouse protein when administered to a human patient, the patients’ immune system will recognize as “foreign”, or non- human, and mount an immune response generating a human anti-mouse antibody response (HAMA). Thus, OKT3’s use was limited to only acute / severe cases. Generation of HAMA presented a major stumbling block for other mAb based therapeutics, there are no additional mouse mAbs approved for human therapeutic use. Initial efforts to capture the promise and potential for mAb therapeutics while minimizing their liabilities, focused on protein engineering based approaches for reducing the amount of mouse sequence, and thereby increasing the amount of human sequence. Second generation improvements generated so-called Chimeric mAbs, which had human sequence in their antibody constant domains and mouse sequence in their variable domains, thus roughly 70 – 80% human sequence, the remainder of the mAb being mouse sequence. Chimeric mAbs have been successful, and are represented by several approved mAb therapeutics. If chimeric mAbs could be successful, the protein engineers contemplated that pushing the amount of human sequence as high as possible could be even more effective. Indeed, the discovery and development of this next “wave”, the so-called Humanized mAbs was a further protein engineering based advance. Typical humanized mAbs range from 90 – 98% human amino acid sequence, and there are many exemplars among the approved human therapeutics.
Third Generation mAb Technologies.
The next evolution was to the so-called Fully human mAbs, where the entire monoclonal antibody is made up of human amino acid sequence. There were two main strategies utilized, transgenic animal systems and in vitro display systems. Transgenic animal systems involve the use of an animal species (most commonly mouse), where the mouse antibody producing genes have been deleted and replaced with human copies of the genes. After immunizing the transgenic animal with the target antigen, hybridomas can be produced, and these generate mAbs with 100% human amino acid sequence. The in vitro display systems can vary in terms of which species is used for display (most commonly this is bacteriophage or simply phage display) as well as the origin of the sequences for the library. Most libraries are either derived from directly isolating antibody producing cells and extracting their DNA from humans (human derived), from synthesized DNA based on canonical human germline antibody producing sequences (synthetic), or a blend (semi-synthetic). Fully human mAbs have been highly successful with dozens having been approved as human therapeutics with positive impacts upon human health worldwide.
i2 Pharmaceuticals’ ConCIRT antibody discovery technology is a leading example of a synthetic phage display technology.
Additionally, innovators have sought to build upon the basic antibody architecture to provide additional functionality embodied with so-called Empowered Antibodies. This has been especially important in the applications for therapeutic mAbs in cancer, where increased potency to kill cancer cells can be required. Among others, the two most clinically and commercially successful approaches to date, have been a) Antibody Drug Conjugates (ADCs), whereby the mAb is chemically conjugated or linked to a cytotoxic payload molecule – in the patient’s body, the mAb acts as a delivery vehicle to bring the ADC to the cancer cell, to internalize into that cell in a target specific fashion, finally to release its payload and rapidly kill such cancer cell, and b) Bispecific antibodies, whereby one arm of the mAb binds to one target protein and the other arm binds to a separate and distinct target protein.
Next Generation – Surrobody Technology.
i2 Pharmaceuticals’ Surrobody Technology is a leading next generation approach with an abundance of advantages compared to current monoclonal antibody discovery technologies. These advantages include, among others:
- Non-antibody composition provides Freedom-To-Operate (FTO) into target spaces blocked to traditional mAbs
- Invariant Surrogate Light Chain (SLC) simplifies and accelerates bispecific discovery and development
- Invariant SLC enables rapid, site-specific drug conjugation for discovery and development of Surrobody Drug Conjugates (SDCs)
- Surrobodies retain the beneficial qualities which have made mAbs so successful as therapeutics, namely antibody-like pharmacokinetics and good manufacturability
- As an in vitro display based discovery approach, Surrobody discovery optimizes many of the inherent advantages of this approach, namely use of very large and highly diverse libraries and an opportunity to get the broadest possible epitope diversity, meaning one ends up with Surrobodies which bind to the target antigen in a wide variety of different locations on the surface of the target antigen, a highly desirable characteristic to drug developers