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Assessment of Affimer® Protein Technology As Critical Reagents in Bioanalytical Pharmacokinetic (PK) Methods Amy Reeves, Covance Laboratories Ltd, Harrogate, UK

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Assessment of Affimer® Protein Technology As Critical Reagents in Bioanalytical Pharmacokinetic (PK) Methods Amy Reeves, Covance Laboratories Ltd, Harrogate, UK Assessment of Affimer® Protein Technology as Critical Reagents in Bioanalytical Pharmacokinetic (PK) Methods Amy Reeves, Covance Laboratories Ltd, Harrogate, UK Introduction System Suitability and Range of Quantitation Table 2. Difference from Baseline in Accuracy and Precision of Low and High QC Samples The calibration curve spans a 33-fold quantifiable range from 60 to 2000 ng/mL Antibodies currently represent the “gold standard” of affinity reagents used in – greater than double the working range of the current antibody based method. QC %CV %Bias regulated bioanalysis of therapeutic proteins. Over time, traditional antibodies Standard curve profiles from 6 independent runs are comparable (Fig 4), with have been refined to the point where they are specific, sensitive, and reasonably LQC 1.8 1.8 cumulative recoveries across concentrations within ± 7.5% of nominal, and reliable. Yet, monoclonal and polyclonal antibodies remain limited by their precision (%CV) across standard curve points of ≤ 10.8%. HQC 0.3 2.8 significant size, poor stability and batch-to-batch variation in assay performance. ® Dilutional Linearity What is an Affimer ? The Affimer® (Avacta Life Sciences, UK) is a novel artificial binding protein Dilutional linearity samples above the ULOQ generated a response < ULOQ, (ABP) based on a consensus sequence of plant Cystatin A (Tiede et al., 2014). while samples prepared to a concentration below the LLOQ generated a The Affimer® protein scaffold is biologically inert, biophysically and biochemically response < LLOQ. Samples within the working range were quantified against stable and can be engineered (via peptides inserted at loop 1, loop 2 and the their respective calibration curve and back-calculated concentrations were within amino terminus) for highly specific, high-affinity interactions (Stadler et al., 100% (+/- 20%) (+/- 25% at the assay limits) of the nominal concentration. 2011). Candidate Affimer® binders can be rapidly developed in up to 12 weeks, meaning quicker assay development time and cost. Table 1 summarises the key ® differences between Affimers and Antibodies. Very small 14 kDa Simple Figure 4. Inter-assay calibration curve performance. Single chain, no S-S bonds Accuracy and Precision (A&P) Evaluation Extreme stability Up to 100 °C The individual back-calculated QC concentrations generated from the standard Stable in a broad pH range curve had intra-assay CVs ≤ 12.4%, and accuracy within ± 10.8% of nominal (n=6) (Fig 5A). Cumulatively, the individual back-calculated QC concentrations Large phage libraries generated generated from standard curves across 3 assays had inter-assay CVs ≤ 19.4%, High complexity of 80% and accuracy within ± 4.2% of nominal (n=9) (Fig 5B). 10 size: >2.3x10 Easy to engineer Figure 8. Dilutional linearity assessment. Insertion of cysteines A Multimers for multispecificity 15 % B ia s ® 10 Lot-to-Lot Consistency of Affimer Reagent Well expressed in E.coli % CV 5 Affimers® from multiple production lots (n=4) were assessed in concurrently run 0 A+P assays to investigate the degree of lot-to-lot variation in critical reagent ® % Table 1. Affimers vs. Mono- and Polyclonal Antibodies ® performance. Standard curve profiles of Affimers from 4 production lots are Monoclonal Polyclonal -5 Feature Affimers® comparable (Fig 9). Antibodies Antibodies -10 Size ̴ 14kDa ̴ 150kDa Variable -15 LLOQ LQC MQC HQC ULOQ Development 10-12 weeks 4.5-6 months 2-4 months QC Level Duration Manufacturing Costs Low High Low B Manufacturing Bacterial expression Recombinant DNA Species % B ia s Process (E.coli) technology immunisation 20 % CV Yield Up to 200mg/mL 1-10 g/L Variable Ease of Engineering High More difficult Difficult ∼ 10 Specificity High and controllable Not always high Low % Sensitivity High Low High 0 Melting Temperature 42 -100°C 40 to 70 °C 40 to 70 °C (Tm) Lot-to-Lot Quality High Not always high Low – biological -10 Consistency variability Figure 9. Comparability assessment of lot-to-lot Affimer® LLOQ LQC MQC HQC ULOQ Multiple Target Easy Impossible Easy performance: system suitability. QC Level Binding Figure 5. A&P runs: (A) intra-assay A&P (VS samples n=6); (B) inter-assay A&P (n=9). Methods The individual back-calculated QC concentrations generated from each respective standard curve had inter-assay accuracy and precision within target Methodology has been designed to assess a candidate Anti-Trastuzumab The quantitation limit (LoQ) and/or sensitivity for this analytical procedure is acceptance criteria, demonstrating lot-to-lot consistency in assay performance Affimer® binder in a bioanalytical PK ELISA sandwich format for Trastuzumab validated to be 60ng/mL of Trastuzumab, a +20ng/mL difference compared to (Table 3). (Herceptin®, Genentech, South San Francisco, CA) (Fig 2). Bioanalytical the current antibody based PK method. method development included all the applicable regulatory specified validation parameters (EMA, 2011; FDA, 2013) . ® Selectivity in Disease-State Matrix Table 3. Comparability Assessment of Lot-to-Lot Affimer Performance: Inter-Assay A&P of QC Samples Evaluation of selectivity was performed using a panel of 9 human donor metastatic breast cancer serum samples spiked with Trastuzumab at a slightly QC Lot #1 Lot #2 Lot #3 Lot #4 Inter-Assay raised assay LLOQ (100µg/mL). 1 -7.5ᵡ 0.7 -2.5 -12.7 -5.5 LLoQ 2 5.9ᵡ 2.2 7 5.2 7.3 20 -5.7 -2.5 -7.8 -7.9 -5.6 LQC 0.3 1.4 5.1 -7.9 4.5 -7.9 -0.1 -11.4 16.8 -2.5 10 MQC 8.8 6.4 9.2 9.8 14.2 -11.7 -11.8 -14.1 -6.2 -10.9 HQC 0 10.4 16.9 2.5 11.4 10.4 Figure 2. Affimer®-based sandwich ELISA format. -21.6 -12.7 -22.7 -9.3 16.2 ULoQ -10 19.5 19.9 13.4 13.9 -16.6 ᵡ1 Accuracy (%bias of nominal) % Bias from Nominal from % Bias 2 Results -20 ᵡ Precision (%CV) 2 4 5 6 7 8 9 Reagent Optimization Summary Individual Human Serum Donors (n=7) The checkerboard approach was used to determine the following optimal This work demonstrates a high performance Affimer® assay to detect and quantify the breast cancer drug Trastuzumab in Human Serum, both normal and concentrations of critical reagents: Figure 6. Selectivity assessment at the LLOQ in ® disease-state. The method shows good sensitivity and increased assay dynamic ▶ Capture reagent: Anti-Trastuzumab Affimer Clone B3 at 1.04µg/mL human metastatic breast cancer serum donors range compared to the current existing antibody based method. Affimers® from ▶ Detection reagent: Biotinylated Anti-Trastuzumab monoclonal antibody at (60ng/mL nominal). independent production lots performed comparably in the validated method, 1.00µg/mL ▶ Enzyme Conjugate: Streptavidin-HRP at 1 in 2000 dilution demonstrating consistency in lot-to-lot Affimer® performance. These data ® Benchtop Stability validate the scope of Affimer protein technology used as alternatives or complementary critical reagents to traditional antibody molecules in regulated ® Method Selectivity Bench-top stability of the Affimer as a coating reagent was assessed by storing PK assays for therapeutic antibodies. a single-use vial at ambient room temperature (ART) for a targeted exposure of Recovery of Trastuzumab at a 1 in 10 Minimum Required Dilution (MRD) is 24 ± 4 hours prior to plate coating. Standard curve responses of baseline within the established method accuracy (%bias) and precision (%CV) Affimer® and stored Affimer® were comparable (Fig 7) and % difference from acceptance criteria for >80% of the standards tested. A 1 in 10 MRD was References baseline of back-calculated concentrations of QC samples against stored therefore chosen as the dilution needed to minimise matrix interference. European Medicines Agency. 2011. Guideline on Bioanalytical Method Validation. Affimer were within stability target specifications (Table 2). Stadler, L., et al. 2011. Structure-function studies of an engineered scaffold protein derived from Stefin A. II: Development and applications of the SQT variant. Protein engineering, design & selection : PEDS. 24. 751-63. Tiede, C., et al. 2014. Adhiron: A Stable and Versatile Peptide Display Scaffold for Molecular Recognition Applications. Protein Eng Des Sel. 27(5), pp. 145-55. U.S. Food and Drug Administration (FDA). 2013. Guidance for Industry: Bioanalytical Method Validation. Figure 3. Assessment of matrix interference at a 1 in 10 MRD. Figure 7. Calibration curve performance of baseline Affimer® vs. stored Affimer®. Presented at EBF 2017 .
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