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Study finds the biosimilar ABP 654 and ustekinumab do not have clinical meaningful differences according to the step-wide totality-of-evidence approach and thus have similar psychochemical and biological properties.
The biosimilar ABP 654 has analytically similar psychochemical and biological properties, including structure, function, purity, and potency to the reference product, ustekinumab (Stelara®), according to new research.1
Ustekinumab treats forms of plaque psoriasis, active psoriatic arthritis, Crohn’s disease, and ulcerative colitis.2 While ABP 654 is a biosimilar of ustekinumab, the two products use different expression systems. Ustekinumab is expressed in a Sp2/0 cell line system, and ABP 654 is expressed in a Chinese hamster ovary (CHO) cell line system, glycol-engineered to enrich bio-similarity to ustekinumab.1
The new study, led by Greg Cantin, PhD, a principal scientist of biosimilars at Amgen in Thousands Oak, California, sought to evaluate the analytical similarity between ABP 654 and ustekinumab. The analytical testing plan examined general properties, primary structure, higher-order structure, product-related substances and impurities, particles and aggregates, biological activity, and thermal stability and degradation studies.
“There were some minor differences in physiochemical attributes observed between ABP 654 and ustekinumab [reference product], primarily due to the different cell lines used between ABP 654 and ustekinumab [reference product],” wrote the investigators. “However, results of the biological and functional assessments showed that these minor physicochemical differences do not affect biological functions relevant to the mechanism of action of ABP 654 and ustekinumab.”
Cantin and colleagues followed the step-wide totality-of-evidence approach, which is the recommend guideline in the United States and the European Union to gain biosimilar regulatory approval. The approach demonstrates whether the results have clinically meaningful differences in safety or efficacy between the biosimilar and the reference product (in this case, ustekinumab).
The investigators completed several analytical assessments, including:
The team also examined higher-order structure through a secondary structure assessment and a tertiary structure.
Aside from the analytical assessments, the investigators conducted many functional assessments, such as:
Cantin and colleagues used these assessments based on their knowledge regarding the structure, function, and heterogeneity of ABP 654 and ustekinumab.
The team accessed amino acid sequence using the reduced peptide map analysis and found that ABP 654 and ustekinumab are, as hypothesized, within 100 ppm of their theoretical masses. While the peptide map profiles for both products are similar, due to their different cell lines they have minor differences with their glycosylation profile and C-terminal lysine level differences.
Despite the differences, the investigators wrote how ABP 654’s CHO-derived N-acetylneuraminic acid (NANA)-containing glycans and ustekinumab’s Sp2/0-derived N-glycolylneuraminic acid (NGNA)-containing glycans should not have clinical efficacy issues as there was no observed difference in biological activity.
“Results from reduced peptide mapping demonstrated that the amino acid sequence of ABP 654 was identical to that of ustekinumab,” the investigators wrote.
The team also compared levels of identified post-translational modifications in ABP 654 and ustekinumab and found that levels of the two are similar. As for C-terminal lysine level, ABP 654 had a lower level compared with ustekinumab and thus not viewed as “clinically meaningful.”
The biosimilar and reference product showed similar results with the sialyl glycan peaks after ABP 654 went through neuraminidase Au treatment. Meanwhile, the investigators found that ABP 654 had roughly 3% lower levels of afucosylation compared with ustekinumab, which could be due to the lower FcγRIIIa binding activity. Though, despite the lower levels of afucosylation, the investigators wrote how it does not have a clinically meaningful impact since ABP 654 and ustekinumab do not provoke effector functions.
For β-galactosylation, ABP 654 had higher levels with an approximate 5% difference compared to ustekinumab. The greater level had no effect on biological activity since C1q-binding activity is comparable to ustekinumab. Therefore, again, the difference in β-galactosylation was not clinically meaningful.
Similarly, ABP 654 had greater levels for sialyation, but the approximate 4% difference was not “clinically meaningful.” The same thing applied to the SE-UHPLC profiles which assessed size variants—the difference was < 0.5%.
“Size variants for ABP 654 and ustekinumab [reference product] were considered similar, notwithstanding minor differences that are not considered clinically meaningful,” the investigators wrote. “Charge variants for ABP 654 and ustekinumab [reference product] were considered similar after excluding C-terminal lysine and glycans from the analyses.”
ABP 654 and ustekinumab had similar binding to IL-23 and IL-12, as well as having similar IL-23 and IL-12 for mediated signaling. Ultimately, the study’s results showcased ABP 654’s similarity to ustekinumab.
“While there were some minor differences in ABP 654 compared with ustekinumab [reference product], these were not considered to be clinically meaningful and are unlikely to have an impact on [pharmacokinetics], efficacy, or safety,” the investigators wrote.