Shortening mAb development timelines with accelerative CMC strategies

How non-clonal cell lines (SBCs) can add value to the biologics supply chain

By the middle of 2022, 162 therapeutic antibodies had been approved by the FDA¹, treating cancer, diabetes, infectious disease, and autoimmune disease with high specificity and low side effects. However, the number of diseases with biotherapeutic based standards-of-care is still low relative to the number of diseases that could be addressed by therapeutic antibodies. As scientists continue to elucidate more of these druggable targets, the number of novel drug modalities increases and speed-to-clinic becomes an imperative for the industry and patient care.

Developers of next-gen medicines face increasing risks due to increasing complexities

As market complexity increases so too does risk, due to competing priorities and timeline horizons among investors, developers, and outsourcing providers.

With Seed dollars, investors need to see that there is a development path and a competitive advantage within the landscape. Meanwhile, innovators face increasing R&D costs while striving to generate in vivo data for therapeutic rationale in key indications, often with insufficient animal models.

With Series A dollars, investors historically wanted to finish IND enabling studies, get close to the clinic, and build out a team to execute the plan. Innovators needed to demonstrate robust in vivo data to show a benefit over standard-of-care or competitor, a clear clinical development plan and timelines to human data.

Series B funding supports the phase 1 testing plan investors need to see a clear path to exit; either an IPO or acquisition based on successful clinical data. They also need to be confident that their money is not just paying for CMC and scale-up, but that it will achieve proof of concept, even with some expected delays.

Fundraising milestones are largely dependent on developers’ having timely and ease-of-access to reliable, reproducible materials, that are representative of future clinical trial materials; often from outsourcing providers like CDMOs. However, over the last few years, investors have become increasingly risk averse and are asking innovators to deliver more data in shorter timeframes.  Today’s fundraising environment is such that innovators are being asked for preliminary clinical data to come from Series A dollars which used to be reserved mostly for IND-enabling activities^2,3.  In the face of rising costs, and speed-to-clinic pressures by investors, the relationship between innovators and outsourced development/manufacturing providers is more critical than ever.

A change in cell line development services to accelerate time to clinic

Automation, digitalization, and platforms play an essential role in reducing monoclonal antibody development timelines.  However, some platforms are very time consuming in their design and purpose.  For example, current FDA⁴ and ICH⁵ require that biological substances be produced from cultures derived from single-cell clonal lines (vis-à-vis stable cell line development or CLD).  CLD remains a significant and costly bottleneck in the development of new monoclonal antibody therapeutics adding months to the development timeline and requiring significant portion of Series A funding.  This outlay of large capital for CLD represents a big gamble of funds prior to the acquisition of any preclinical or clinical data supporting the safety, efficacy, or manufacturability of the therapeutic candidate.

The use of cultures derived from non-clonal cell lines (stable bulk cultures or SBCs) to produce materials can speed up the development process for investigational drugs.  This speed-to-clinic concept has been an emerging CMC (chemistry, manufacturing, and controls) strategy contemplated in the literature for the last decade, but not yet widely adopted.

This strategy was thrust into practice during the COVID-19 public health emergency (PHE) for numerous SARS-CoV-2 neutralizing antibody products that received FDA Emergency Use Authorization (EUA).  It  was a critical timeline compression factor that enabled a rapid response to the PHE. Given the recent regulatory exposure to this rapid-CMC approach, an industry-wide trend has started to emerge showing an increasingly broader adoption of SBCs for material production.

Enabling tools for producing reliable, reproducible, and representative materials from SBCs includes high producing, well characterized, GS-null CHO parental cell lines, transposon-mediated gene delivery systems to create the non-clonal cell lines, and well characterized, platform cell culture processes to create the SBCs. Transposons are key to maintaining the quality of the SBC.  This modality of cell line development minimizes phenotypic variability among cells in the SBC and increases the likelihood that the phenotypes of derivative single cell clonal lines will be comparable to that of the SBCs. With well integrated/compatible processes, the process for scaling up non-clonal cell lines to SBCs are the same as for derivative single cell clonal lines, de-risking further the eventual manufacturing change required for market approval.

Portable CMC™: Speed, efficiency, predictability, and freedom

Wheeler Bio is transforming the CDMO model. Our Portable CMC™ platform, developed at our central US location, shifts the paradigm on biomanufacturing quality, clinical timelines, and customer experience.

Portable CMC™ is a package of innovative services that solves one of the most critical challenges in biologics development — the translation from lab discovery into efficient, scalable manufacturing. Using state-of-the-art tools, technologies, data science and original methods for drug substance manufacturing and testing, Portable CMC™ provides an efficient bundling of three useful CMC development modules — Lead Selection, Clone Selection, and CDMO Selection.  There are 10 work packages tied to the three modules with agile optionality that results in a new tier of accessibility for venture backed biotechs.

Portable CMC™ comprises three service modules and ten integrated work packages:

1. 1. Lead Selection: non-clonal cell line development services and SBC evaluation

Lead Selection provides an easy to access and fast option for generating highly representative materials, early product quality attribute (“PQAs”) assessments, manufacturability data, and materials for additional developability considerations to reduce the risk of lead molecule selection in the mAb discovery process. Wheeler leverages industry leading and FDA-accepted Leap-In Transposase® (ATUM) to enable a cost-effective, easily implemented cell line development workflow, delivering high productivity non-clonal cell lines with pool-to-pool consistent product quality.  Pools are scaled to SBCs and tested from shake flask and in bench-top bioreactors using Wheeler’s well characterized cell culture process.  This module results in a primary and backup SBC plus comprehensive analytical reporting.

2. 2. Clone selection: a clonal cell line development service

Clone Selection utilizes state-of-the-art technologies and automated workflows with built-in platform assessments to generate development cell banks (“DCBs”) and master cell banks (“MCBs”) for up to two (2) lead molecules. Clients benefit through unsurpassed confidence of clonality with the Solentim® Ecosystem, reduction of clone selection risk by incorporation of the Ambr® 15 bioreactors data, and accelerated timelines to an MCB.  Wheeler leverages the same Leap-In Transposase® system to deliver high productivity clonal cell lines with pool-to-clone comparability.  The workflow starts with frozen SBCs for seamless integration with Lead Selection.  A final work package provides for genetic stability assessment.

3. 3. CDMO selection: scale-up tox and clinical material generation with cell substrate optionality plus open-source tech transfer and CMC regulatory work packages

CDMO Selection provides an easy-to-access rapid supply of material for toxicology studies, high-quality CGMP supply of material for clinical studies, qualified DS release methods, and an open-source scalable manufacturing process with a CMC transfer strategy based upon Wheeler’s platform process and technical expertise. Clients benefit through early access to toxicology materials to initiate IND-enabling studies, production of CGMP materials with all documentation and stability data to support IND filing requirements, and the freedom and support to tech transfer the manufacturing process to any CDMO to prepare for late clinical phase and commercial phase manufacturing.

A new tier of customer experience

Wheeler’s Portable CMC™ platform is underpinned by our steadfast commitment to collaboration, data transparency, and Pharma 4.0. Our platform is a focused and purpose-built enterprise enabling a new tier in customer experience. We have developed unique service modules that are designed to be easy to access with thoughtful alignment of services to match fundraising process. Rapid pool-based workflows enable speed-to-clinic and an open-source platform for de-risking scale-up and tech transfers. A well-integrated tech stack with digital solutions helps to generate more insights into product and process. When integrated with antibody discovery processes, innovators benefit from:

• Predictable yields, timelines, and budgets
• Reduced regulatory risks during IND filings
• A standardized, freely transferable suite-ready manufacturing CMC package
• Open-source drug substance process with the freedom to go to any manufacturer
• Fixed fees, cost-efficiency, and transparent collaboration

References

1. 1. Lyu X, Zhao Q, Hui J. et al., The global landscape of approved antibody therapies. Antib Ther. 2022 Sep 6;5(4):233-257.
2. 2. Healthcare Investments and Exits 2020, Silicon Valley Bank
3. 3. Senior, Melanie. Precision Financing. Nature Biotechnology. 27 April 2023
4. 4. Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use.S. Food and Drug Administration. Center for Biologics Evaluation and Research. 1997.
5. 5. ICH Q5D: Derivation and characterisation of cell substrates used for production of biotechnological/biological products – Scientific guideline. 31 Mar. 1998.