Alameda- (California-) based Exelixis confirmed that it has signed a partnership agreement with Catalent to develop multiple antibody-drug conjugates (ADCs) using Catalent’s proprietary SMARTag® site-specific bioconjugation technology.
Under the terms of the agreement, Catalent will use its proprietary SMARTag® bioconjugation platform to build novel ADCs using antibodies from Exelixis’ growing preclinical pipeline. In exchange for an upfront payment to Catalent of U.S. $ 10 million, Exelixis received an exclusive option to nominate up to a fixed number of targets using the SMARTag® ADC platform over a three-year period.
The companies plan to advance the ADCs into preclinical development, and, prior to filing an Investigational New Drug application (IND), Exelixis may exercise its exclusive option to a worldwide license of the related ADC program and continue clinical development and commercialization.
Exelixis will also provide research & development funding, while Catalent will be eligible for development and commercial milestones and royalties on net sales of any product commercialized as part of the collaboration.
Based on cell-specific recognition and the binding of an antigen by an antibody, ADCs offer the ability to target the delivery of a cytotoxic drug to specific cancer cells. In doing so, ADCs have, in comparison with traditional chemotherapeutic treatments, provided a breakthrough in the treatment of cancer and hematological malignancies by increasing efficacy and decrease toxicity.
However, the manufacturing of early generations of ADCs, using conventional heterogeneous conjugation methods, have resulted in heterogeneous mixtures, with different ADC species, in which cytotoxic payloads are attached to an antibody via chemical conjugation to endogenous lysine or cysteine residues. Each of these ADC species has individual characteristics concerning pharmacokinetics, toxicology, and efficacy. Site-specific conjugation helps circumvent this.
Catalent’s SMARTag® technology platform, developed by the company’s Redwood Bioscience* subsidiary, provides optimized site-specific protein-modification and linker technologies for ADCs and other bioconjugates. The technology overcomes the limitations associated with traditional protein chemistries that produce heterogeneous products with variable conjugate potency, toxicity, and stability and enables the development of ADCs with a wider therapeutic window and improved manufacturability.
The technology employs natural post-translational modifications found in human cells to create one or more aldehyde tags at designated sites on protein molecules. These chemical “handles’’ are then stably conjugated to payloads (e.g., cytotoxic or effector) to prevent their systemic release.
Catalent’s SMARTag® technology platform provides precise payload positioning, stable, site-specific conjugation, and defined stoichiometry of drug-protein ratios. The control afforded by the technology enables the identification of superior drugs from libraries of differentially designed conjugates.
“The SMARTag® platform has recently demonstrated promising results in the clinic, highlighting the potential to create ADCs with significantly expanded therapeutic indices,” commented Mike Riley, Region President, Catalent Biologics, North America.
Focus on cancer
Exelixis focuses on the development of anti-cancer agents. The company’s rationale is that cancer is an elusive and complex, pervasive, and diverse disease, and while much progress has been made in the treatment of cancer and hematological malignancies, it remains one of the most challenging diseases of our lifetime. Cancer is adaptive in nature and, as a result, requires a formidable approach to really understand tumor genesis and how treatments can be devised to suppress and kill cancer cells.
To date, Exelixis’ research and development efforts have resulted in three small molecule therapeutics with broad potential in the treatment of cancer. The first novel drug to emerge from the company’s pipeline was cabozantinib (Cabometyx® and Cometriq®), a small molecule inhibitor of tyrosine kinases MET, AXL, RET, VEGFR2, and others, which are involved in both normal cellular function and pathologic processes, such as tumor growth, metastasis, and angiogenesis. The medication is used to treat medullary thyroid cancer and is a second-line treatment for renal cell carcinoma among others.
“With our lead product cabozantinib now a global oncology franchise, over the past several years Exelixis has moved beyond our small molecule medicinal chemistry roots to build out a pipeline that encompasses a variety of promising therapeutic modalities,” said Peter Lamb, Ph.D., Executive Vice President, Scientific Strategy and Chief Scientific Officer of Exelixis.
Supported by revenues from the company’s marketed products, including cabozantinib, Exelixis is committed to reinvesting funds to maximize the potential of their pipeline.
“Our collaboration with Catalent – the fifth pipeline-enhancing agreement we’ve signed since 2018 – provides an attractive framework for identifying and advancing differentiated ADC product candidates with the potential to improve upon current ADC therapies. We are looking forward to working with Catalent as we rapidly advance our mission to help cancer patients recover stronger and live longer.”
“We are excited to partner with Exelixis, a leading oncology biotechnology company, and leverage our experienced team, unique SMARTag® technology platform, and deep analytical expertise to develop ADCs targeting various oncology indications,” Catalent’s Riley concluded.
 Yamada K, Ito Y. Recent Chemical Approaches for Site-Specific Conjugation of Native Antibodies: Technologies toward Next-Generation Antibody-Drug Conjugates. Chembiochem. 2019;20(21):2729-2737. doi:10.1002/cbic.201900178
 Liu J, Barfield RM, Rabuka D. Site-Specific Bioconjugation Using SMARTag® Technology: A Practical and Effective Chemoenzymatic Approach to Generate Antibody-Drug Conjugates. Methods Mol Biol. 2019;2033:131-147. doi:10.1007/978-1-4939-9654-4_10
 Rupniewski I, Rabuka D. Site-Specific Labeling of Proteins Using the Formylglycine-Generating Enzyme (FGE). Methods Mol Biol. 2019;2012:63-81. doi:10.1007/978-1-4939-9546-2_5
Catalent acquired Redwood Bioscience in 2014.
Featured image: Catalent at the annual CPhI World Wide congress and exhibition being held in Barcelona, Spain, June 4 – 6, 2016.