Scientific and statistical considerations in evaluating the analytical similarity of ABP 501 to adalimumab.

Analytical similarity is the foundation of the totality-of-evidence-based approach for demonstrating that a proposed biosimilar is highly similar to a reference product. This review uses analytical similarity assessment of ABP 501, the first approved adalimumab biosimilar, as a case study to highlight considerations necessary to demonstrate analytical similarity. Similarity assessments start with risk-ranking the critical quality attributes based on scientific understanding of how they impact safety, efficacy, immunogenicity and/or pharmacokinetics/pharmacodynamics.

Hsp70 chaperone ligands control domain association via an allosteric mechanism mediated by the interdomain linker.

Hsp70 chaperones assist in protein folding, disaggregation, and membrane translocation by binding to substrate proteins with an ATP-regulated affinity that relies on allosteric coupling between ATP-binding and substrate-binding domains. We have studied single- and two-domain versions of the E. coli Hsp70, DnaK, to explore the mechanism of interdomain communication.

Dependence of endoplasmic reticulum-associated degradation on the peptide binding domain and concentration of BiP.

ER-associated degradation (ERAD) removes defective and mis-folded proteins from the eukaryotic secretory pathway, but mutations in the ER lumenal Hsp70, BiP/Kar2p, compromise ERAD efficiency in yeast. Because attenuation of ERAD activates the UPR, we screened for kar2 mutants in which the unfolded protein response (UPR) was induced in order to better define how BiP facilitates ERAD. Among the kar2 mutants isolated we identified the ERAD-specific kar2-1 allele (Brodsky et al.