No abstract

5 g tumor mass). In contrast, unconjugated CalichDMH, unconjugated G5/44, and an isotype-matched control conjugate, CMA-676, were ineffective against these BCL xenografts. Thus, CD22-targeted delivery of CalichDMH is a potent and effective preclinical therapeutic strategy for BCLs. The strong antitumor profile of CMC-544 supports its clinical evaluation as a treatment option for B-lymphoid malignan-

No abstract

Antibody-drug conjugates (ADCs) typically consist of a cytotoxic drug covalently bound to an antibody by a linker. These conjugates have the potential to substantially improve efficacy and reduce toxicity compared with cytotoxic small-molecule drugs. Since ADCs are generally complex heterogeneous mixtures of multiple species, these novel therapeutic products present unique bioanalytical challenges. The growing number of ADCs being developed across the industry suggests the need for alignment of the bioanalytical methods or approaches used to assess the multiple species and facilitate consistent interpretation of the bioanalytical data. With limited clinical data, the current strategies that can be used to provide insight into the relationship between the multiple species and the observed clinical safety and efficacy are still evolving. Considerations of the bioanalytical strategies for ADCs based on the current industry practices that take into account the complexity and heterogeneity of ADCs are discussed.

The present work demonstrates that high hydrostatic pressure can increase protein folding by reducing nonspecific aggregation. Protein aggregation is one of the main side reactions that competes with protein folding, and it typically results from interactions among partially folded intermediates. It is known that oligomeric proteins can be dissociated by the application of high hydrostatic pressure. Since protein aggregates can be described as nonspecific protein oligomers, it can be predicted that they can be completely or partially dissociated by pressure. The enzyme rhodanese is prone to slow aggregation in 3.9 M urea, and it is widely used as a model for the folding of a protein which readily aggregates. In the present study, it was demonstrated that this aggregation process could be completely reversed under high hydrostatic pressure. Release of the pressure led to renewed protein aggregation. In addition, it was demonstrated that refolding of urea-denatured rhodanese at 2 kbar pressure led to an increased yield of the native enzyme. The final recovery was increased up to approximately 25% in contrast to approximately 5% recovery observed under ambient pressure. The recovery can be further increased in the presence of 4 M glycerol, where 56% of the protein was recovered by treatment with high pressure. These observations suggest that some protein aggregation can be limited without the use of chemical additives, and they show that the pressures needed to maintain solubility are considerably less than those typically required for dissociation of specific oligomers and unfolding of polypeptide chains.