A strategy to accelerate protein production from a pool of clones in Chinese hamster ovary cells for toxicology studies

Abstract

In the biopharmaceutical industry, a clonally derived cell line is typically used to generate material for investigational new drug (IND)-enabling toxicology studies. The same cell line is then used to generate material for clinical studies. If a pool of clones can be used to produce material for IND-enabling toxicology studies (Pool for Tox (PFT) strategy) during the time a lead clone is being selected for clinical material production, the toxicology studies can be accelerated significantly (approximately 4 months at Genentech), leading to a potential acceleration of 4 months for the IND submission. We explored the feasibility of the PFT strategy with three antibodies-mAb1, mAb2, and mAb3-at the 2 L scale. For each antibody, two lead cell lines were identified that generated material with similar product quality to the material generated from the associated pool. For two antibody molecules, mAb1 and mAb2, the material generated by the lead cell lines from 2 L bioreactors was tested in an accelerated stability study and was shown to have stability comparable to the material generated by the associated pool. Additionally, we used this approach for two antibody molecules, mAb4 and mAb5, at Tox and GMP production. The materials from the Tox batch at 400 L scale and three GMP batches at 2000 L scale have comparable product quality attributes for both molecules. Our results demonstrate the feasibility of using a pool of clonally derived cell lines to generate material of similar product quality and stability for use in IND-enabling toxicology studies as was derived from the final production clone, which enabled significant acceleration of timelines into clinical development. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1449-1455, 2017.

Enabling speed to clinic for monoclonal antibody programs using a pool of clones for IND-enabling toxicity studies

“…With this approach, it takes longer to get to first-in-human trials in our experience, mostly because the IND-enabling Tox study is on the critical path. Recent reports indicate that industry is adapting the “pool of clones” strategy for Tox material generation, 12 , 13 and early development timeline can be shortened by as much as 4 months. 12

Figure 1.

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“…Recent reports indicate that industry is adapting the “pool of clones” strategy for Tox material generation, 12 , 13 and early development timeline can be shortened by as much as 4 months. 12

Figure 1. Standard cell line development and process workflow at BMS.

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Generation of High Expressing Chinese Hamster Ovary Cell Pools Using the Leap‐In Transposon System

“…With the goal of accelerating the new drug approval process, the biopharmaceutical industry has made several efforts to shorten the time of new drug development. One time‐saving approach is the use of CHO cell pools to generate material for Good Laboratory Practice‐Toxicology (GLP‐Tox) or potentially even First In Human (FIH) studies …”

“…The term “CHO cell pool” has been interpreted in several ways − (i) mini‐pools (small pools of stably transfected cells); (ii) pool of multiple top CDCLs; and (iii) the population of recombinant cells obtained by transgene delivery and genetic selection . In all above cases the cell pool was not a population originating from a single cell.…”

Introduction to special section on using pools to generate Good Laboratory Practice tox or other non‐clinical material to accelerate development timelines

“…In all of the articles, at least one variation of a pool population is compared to clones producing the same mAb (or Fc‐fusion protein) and the implications of the data are discussed. In some cases, mixtures of clones are described, while other examples speak to the degree of homogeneity of uncloned pools …”