Removal of host cell proteins (HCPs) during biotherapeutics manufacturing is vital for ensuring patient safety and biotherapeutic stability and supply. Yet, this goal remains exceptionally challenging for some HCPs. For example, phospholipase B-like 2 (PLBL2) from Chinese hamster ovary (CHO) cells (the workhorse for therapeutic protein production) plagues engineers by evading typical purification strategies. New tools have emerged to aid HCP removal, but technologies directed at specific HCP species are still nascent, and an urgent, unmet need remains. Herein, we present a platform approach for the targeted removal of specific, challenging HCPs – even those present at sub-ppm levels. Using CHO PLBL2 as a model, we site-specifically modify and immobilize polyclonal antibodies directed against CHO PLBL2, which exists as multiple proteoforms (e.g., size and charge variants). The immobilized antibodies retain their antigen binding, enabling capture and clearance of CHO PLBL2 from an array of bioprocess streams, including IgG4 and IgG1 antibodies. Although centered on CHO PLBL2, our approach should be broadly applicable to numerous other HCPs across the increasingly diverse biotherapeutic landscape. Additionally, CHO PLBL2 recovered from the polyclonal antibodies exhibits multiple molecular size variants, opening the door to further characterization to identify other proteoforms. This insight can, in turn, guide purification development, even in processes without custom affinity anti-HCP steps.
