The development and manufacture of antibody-drug conjugates (ADCs) requires expertise in both biological drug substance and chemical active pharmaceutical ingredient (API) technologies. The need for contract development and manufacturing organizations (CDMOs) to provide the full spectrum of services for this rapidly growing drug type for enhanced patient treatment is rising.
ADCs have attracted significant interest due to the success of the first two FDA-
approved products — Adcetris® (brentuximab vedotin from Seattle Genetics) and Kadcyla® (ado-trastuzumab emtansine from Genentech). These complex drugs consist of three components — an antibody conjugated using linker chemistry to a small molecule, highly potent payload. This design enables targeted delivery of a cytotoxic agent to the site of interest, significantly increasing efficacy while reducing side effects seen with systemically delivered cytotoxic therapies
Not surprisingly, the ADC market is growing rapidly. Different market research firms report compound annual growth rates (CAGR) ranging from 21.82% between 2017 and 2022 (Azoth Analytics)1 to 41.7% from 2016 to 2024 (Credence Research).2 The latter estimates the value of the market for ADCs will grow from $1.3 billion in 2015 to $29.3 billion in 2022.2 The clinical pipeline included 53 molecules as of late 2015, with nearly one-third in phase II or phase III, along with an additional 60 ADCs at the discovery/preclinical stage, according to Roots Analysis.3 Roots Analysis expects approximately 10 new ADC commercial launches through 2025 but pegs the value of the market at a much smaller $10 billion by that year.3
Because ADCs contain both large and small molecule components and involve the preparation and bioconjugation of highly potent compounds, the breadth and depth of expertise and technical capabilities required for their manufacture are extensive.
Development of an antibody with both the desired binding affinity and specificity, attractive physicochemical properties, safety profile, and an efficient, cost-effective process for the production of clinical and commercial material requires protein engineering and cell line development as well as bioprocess development and scale-up expertise. Production of cytotoxic payloads requires specialized manufacturing facilities, equipment and highly trained operators who can perform advanced synthetic chemistry and purification techniques under highly contained conditions. Access to state-of-the art linker technology with the ability to perform the bioconjugation of highly potent payloads to antibodies is also needed.
This requirement for extensive and varied technical expertise has resulted in the outsourcing of most ADC manufacturing — approximately 70%-80%, according to Roots Analysis.3 There are only a few contract manufacturers that offer linker chemistry and cytotoxic payload development, and even fewer that provide ADC bioconjugation services.3
Building on Linker Technology
In recognition of this gap in the CDMO space, Abzena was formed in 2014 following acquisitions by PolyTherics (ThioBridgeTM proprietary ADC linker technology) of Warwick Effect Polymers (low-viscosity polymers for half-life extension) and Antitope (immunogenicity, protein deimmunization and manufacturing cell line development services). Its ADC capabilities were then further expanded with the acquisition in 2015 of PacificGMP (bioprocess development and GMP manufacturing) and The Chemistry Research Solution (TCRS), which provides cytotoxins and chemistry services.
Technology For Lead Candidate Selection
At its Cambridge, UK facility, Abzena offers support at the very earliest stages of development, including discovery, design and characterization of lead candidates. With its many proprietary functional assays and extensive analytical expertise, Abzena not only determines the necessary physicochemical properties (structural conformation, binding affinity, etc.), but also addresses the desired modes of action and safety concerns that might lead to issues in the clinic. Abzena specializes in the construction of customized assays for novel products where “off-the-shelf” assays are not available, especially in the burgeoning immune-oncology sector.
Preclinical immunogenicity assessment to aid lead selection and inform of potential clinical safety and product performance issues is achieved using Abzena’s EpiScreenTM suite of functional assays, which enable determination of the likelihood that a product will induce antidrug antibodies. If a client’s antibody (or other therapeutic biologic) is found to have immunogenicity potential, Abzena can apply its humanization or deimmunization technologies to reduce immunogenicity potential while maintaining the integrity and functionality of the candidate molecule.
Abzena can apply standard methods for humanization of antibodies but also offers a more complete and thorough approach through its proprietary Composite Human AntibodyTM technology. Currently, there are 12 products in the clinic that have used this technology with no antidrug antibody issues reported. Composite ProteinTM technology is also available for the deimmunization of nonantibody therapeutic proteins and has been shown to be effective even for a biologic drug substance that is entirely foreign to humans.
Combined, these technologies help customers design and construct better products. The breadth and depth of scientific knowledge and understanding of the product development process at Abzena is applied on a regular basis to the production and selection of lead candidates with the goal of improving the chances of success in the clinic.
Cell Line Development And Biosimilars Support
For lead product candidates, Abzena can establish research cell banks (RCBs) for manufacturing purposes with experience in many cell lines, including its own proprietary Composite CHOTM cell line. Composite CHOTM is a license-free technology that allows the development of stable and robust RCBs of good productivity. Abzena provides all necessary documentation supporting the clonality and quality of the RCB required for GMP manufacturing.
Biosimilars development is also a core capability of Abzena. The company is one of only a few CDMOs with direct access to and recent experience of successful RCB development of older cell lines used for production of many of the biosimilar biologic opportunities. For example, Abzena has access to a serum-free SP2/0 cell line for biosimilar manufacture. SP2/0 cells were frequently used to produce biologics prior to the popularity of CHO cell lines. With its colocated, sophisticated and advanced bioanalytical capabilities, Abzena is also able to rapidly evaluate the similarity of material produced using these cell lines with the original product for a very streamlined biosimilars development program.
Bioprocess Development And Manufacturing
Development of optimized processes for the non-GMP and GMP production of lead candidates (whether identified by Abzena in Cambridge or elsewhere by clients) takes place in San Diego at the former PacificGMP site. Significant investments are currently being made to upgrade the facility to larger (2 x 500 L plus a third 2,000 L within 12 months), single-use stirred-tank bioreactors. This retrofit is in response to a general demand in the marketplace and the need of many legacy clients with clinical successes for larger-volume production capabilities.
Simultaneously, expansion of process development capabilities at the San Diego facility is underway to help clients develop more robust, predictable processes for GMP production of clinical trial material (up through phase II at present). Installation of an ambr® 250 bioreactor system (from Sartorius Stedim Biotech) for parallel cell culture using 24 x 250 mL SU bioreactors is underway. A plethora of state-of-the-art downstream technologies are also being adopted, with the process development group expanding into a state-of-the-art facility that will support GMP manufacturing. Notably, all of the equipment at the process development, pilot/engineering and manufacturing scales have the same design, allowing rapid scale-up.
Cytotoxic Payload and ADC Linker Manufacturing
The toxic payloads for ADCs, as well as other highly potent and conventional compounds, are produced at Abzena’s Bristol, Pennsylvania site (previously TCRS). The company has a toolbox of more than 20 different payloads for the preparation of ADCs, with extensive expertise in custom synthesis of novel linker-payload variants and chemical moieties.
The facility is currently being modified to add to its fee-for-service chemical synthesis operation, which also provides GMP manufacturing services. The first verification run for monomethyl auristatin E (MMAE, vedotin), a well-known and well-characterized highly potent antimitotic agent, was completed in Q1 2017. Process development services (route design and optimization, troubleshooting, process optimization, etc.) are also available. In addition, Abzena is developing its own proprietary cytotoxic payloads and establishing relevant IP.
To further support ADC manufacture, Abzena is expanding its capabilities to include the GMP manufacture of its ThioBridgeTM linker reagents for coupling toxic payloads to antibodies.
The GMP bioconjugation services at the Bristol facility have progressed, with the site expecting to offer the conjugation of linker-payload molecules with antibodies by early 2018. Three different levels of service will be offered: lab-scale, non-GMP conjugation; non-GMP process development and optimization; and GMP bioconjugation.
In addition to its proprietary ThioBridgeTM linker technology, which allows site-specific conjugation through reaction with the disulfide bond between two cysteines in the antibody without disruption of the tertiary structure of the protein, Abzena can provide a selection of other cleavable and noncleavable linkers and spacer molecules for use with a variety of conjugation technologies. With this choice of approaches, it is possible to optimize the pharmacokinetics and pharmacodynamics of not only ADCs but many other therapeutic peptides and proteins.
To meet the growing demand for ADCs and other antibody-based biopharmaceuticals, Abzena has effectively combined a comprehensive range of emerging technologies to support the full spectrum of activities involved in biologic drug development. Ongoing investments in facilities, equipment and personnel will further enhance the company’s ability to serve as a true partner to developers of innovative therapies and biosimilars. With advanced capabilities in cell line development; antibody, linker and cytotoxic payload production; and bioconjugation, Abzena is positioned to accelerate the development and manufacture of important next-generation therapies to benefit both its clients and their patients.