Blueprint for antibody biologics developability

Mieczkowski, Carl; Zhang, Xuejin; Lee, Dana; Nguyen, Khanh; Lv, Wei; Wang, Yanling; Zhang, Yue; Way, Jackie; Gries, Jean-Michel

doi:10.1080/19420862.2023.2185924

Cited by 20 publications

(14 citation statements)

References 205 publications

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“…For these reasons, the two PTMs were retained but need to be closely monitored in the mAb-A product development. Upon good understanding of the PTMs, a fine formulation 37 can be designed to stabilize mAb-A and mitigate potential risks.…”

Section: Characterization Of Charge Variants At the Subunit Level By ...mentioning

confidence: 99%

In-Depth Characterization of mAb Charge Variants by On-Line Multidimensional Liquid Chromatography-Mass Spectrometry

et al. 2023

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In-depth characterization of charge heterogeneity is a pivotal step desired in the therapeutics antibody development.To this end, a novel on-line multidimensional liquid chromatography-mass spectrometry (MDLC-MS) method for charge variant characterization was developed to dig out potential risks on safety and efficacy. This method implemented 96-well plate fractionation and on-column preconcentration by multi-injection, thereby facilitating detection of charged species at low abundance. Eleven charge variants of mAb-A were preliminarily characterized by 2DLC(CEX × RP-C 4 )-MS. TRVHS and RVHS signal peptide variants of mAb-A were found in basic peaks of the CEX profile. The results supported process development in a timely manner, and the signal peptide-containing variants with potential immunogenicity were successfully removed by an optimized purification process. The retained seven charge variants of mAb-A were further characterized by 4DLC(CEX × RP-C 4 × Trypsin×RP-C 18 )-MS. Post-translational modifications including deamidation, cyclization of N-terminal glutamine, C-terminal lysine truncation as well as proline amidation, and methionine oxidation were identified, and their potential risks were evaluated. Biological activity of the seven charge variants was evaluated by 2DLC (CEX × FcγRIIIa). Increased FcγRIIIa receptor binding affinity was observed in the acidic variants. The MDLC-MS detection can be completed in 72 h with 1.25 mg of mAb, demonstrating to be sample-economic, timeeffective, and labor-saving. It provided a powerful and timely tool for charge variant characterization and met the aggressive timeline desired for antibody development.

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Section: Characterization Of Charge Variants At the Subunit Level By ...mentioning

confidence: 99%

In-Depth Characterization of mAb Charge Variants by On-Line Multidimensional Liquid Chromatography-Mass Spectrometry

et al. 2023

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“…22−24 Developability liabilities add substantial cost and time to drug discovery, reduce efficacy, and may prevent utility altogether. 22,23,25 We define evolvability as the efficiency of the discovery of new functions from a nai ̈ve library; other groups use the term innovability for this property. 10 Yet, as protein size is reduced to yield the aforementioned benefits of small proteins, separation of the framework and paratope is increasingly challenging.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Several of these small proteins have reached clinical trials, and a few have been FDA approved. ,, However, they exhibit a range of performance across metrics, including evolvability and developability. Developability is the set of properties a protein must possess to be translated from the laboratory to genuine use, such as stability, solubility, and cellular expression. − Developability liabilities add substantial cost and time to drug discovery, reduce efficacy, and may prevent utility altogether. ,, We define evolvability as the efficiency of the discovery of new functions from a naïve library; other groups use the term innovability for this property …”

Section: Introductionmentioning

confidence: 99%

Hyperstable Synthetic Mini-Proteins as Effective Ligand Scaffolds

Blanchard,

Knick,

Whelan

et al. 2023

ACS Synth. Biol.

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“…Traditionally, developability screening is performed through a series of laborious in vitro assays (17,22,23). Therefore, major efforts have been invested into developing real-world-relevant in silico tools and machine learning (ML) algorithms that can computationally quantify or predict DP values using antibody sequence and/or structure information (7,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”

Section: Introductionmentioning

confidence: 99%

Biophysical cartography of the native and human-engineered antibody landscapes quantifies the plasticity of antibody developability

Bashour,

Smorodina,

Pariset

et al. 2023

Preprint

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Designing effective monoclonal antibody (mAb) therapeutics face a significant challenge known as “developability”, which reflects an antibody’s ability to progress through development stages based on its physicochemical properties. While natural antibody repertoires may provide valuable guidance for antibody selection, we lack a comprehensive understanding of natural developability parameter (DP) plasticity (redundancy, predictability, sensitivity) and how the DP landscapes of human-engineered and natural antibodies relate to one another. These knowledge gaps hinder fundamental developability profile cartography. To chart natural and engineered DP landscapes, we computed 40 sequence- and 46 structure-based DPs of over two million native and human-engineered single-chain antibody sequences. We found lower redundancy among structure-based compared to sequence-based DPs. Sequence DP sensitivity to single amino acid substitutions varied by antibody region and DPs, and structure DP values varied across the conformational ensemble of antibody structures. Sequence DPs were more predictable than structure-based ones across different machine learning (ML) tasks and embeddings, indicating a constrained sequence-based design space. Human-engineered antibodies were localized within the developability and sequence landscapes of natural antibodies, suggesting that human-engineered antibodies explore mere subspaces of the natural one. Our work charts a roadmap to evaluate the plasticity of antibody developability, providing a more rational perspective for therapeutic mAb design.

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Blueprint for antibody biologics developability

Cited by 20 publications

References 205 publications

In-Depth Characterization of mAb Charge Variants by On-Line Multidimensional Liquid Chromatography-Mass Spectrometry

In-Depth Characterization of mAb Charge Variants by On-Line Multidimensional Liquid Chromatography-Mass Spectrometry

Hyperstable Synthetic Mini-Proteins as Effective Ligand Scaffolds

Biophysical cartography of the native and human-engineered antibody landscapes quantifies the plasticity of antibody developability

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