Physicochemical and Biological Characterization of a Biosimilar Trastuzumab

Table 1

Impact of CQAs on safety and efficacy.

Attribute	Pharmacodynamics	Pharmacokinetics	Immunogenicity
Sequence	Nonspecific	Nonspecific	Determined by the sequence variation against endogenous domains [9]; Differential response due to sequence modifications for distinct batches or processes
Higher order structure	Nonspecific	Nonspecific	Determined by molecular weight and structure complexity [9]
Glycosylation profile	Fucosylated, highly mannosylated, and sialylated variants could alter in vivo efficacy [10–12]	Highly mannosylated variants show higher clearance; Sialylated variants show lower clearance [10–12]	Sialic acid residues can hide antigenic determinants [9, 10]; Highly mannosylated, hybrid, and nonglycosylated variants are prone to elicit immunogenicity
Charge heterogeneity	Effector functions altered if pI differences are >1 unit [10, 14, 15]	Major differences alter volume of distribution and clearance [10, 14, 15]	Acidic variants are prone to elicit immunogenicity [9]
Aggregates	Lower biological activity [11]	Less subcutaneous absorption and lower bioavailability [11]	ADAs presence [10]
FcRI affinity	Affects endocytosis, antigen presentation	Not determined	Not determined
FcRII affinity	ADCC, phagocytosis [17]
FcRIII affinity	Higher affinity to specific variants [11, 12]; Affects endocytosis, antigen presentation, ADCC, phagocytosis [17]
FcRn affinity	Not determined	Lower affinity to acidic variants; Lower affinity for oxidized methionine; Not expected measurable differences in variants with 3- to 4-fold changes in FcRn affinity [16]	Not determined