Pharmacokinetic and Pharmacodynamic Considerations in the Design of Therapeutic Antibodies

Leipold, Douglas D.; Prabhu, Saileta

doi:10.1111/cts.12597

Cited by 35 publications

(35 citation statements)

References 112 publications

(237 reference statements)

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“…It is well established that antibodies with more basic pI values tend to have increased tissue uptake and faster clearance. 46,322 This phenomenon is likely related to the propensity of positively charged residues to interact with negatively charged cell membranes. Reducing the pI of an antibody, for example, by engineering the variable domains, allows for improvement of several PK parameters.…”

Section: Charge and Isoelectric Pointmentioning

confidence: 99%

“…Acidification is thought to decrease interactions at cell surfaces, decrease nonspecific tissue uptake, decrease clearance, and increase bioavailability. 322 On the other hand, increasing pI tends to increase clearance and volume of distribution but could possibly be used to favor penetration of the blood-brain barrier. Significant changes in PK properties have been proposed to occur only once the pI has been changed by >1 pH unit.…”

Section: Charge and Isoelectric Pointmentioning

confidence: 99%

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Considerations for the Design of Antibody-Based Therapeutics

Goulet

Atkins

2020

Journal of Pharmaceutical Sciences

201

154

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Keywords: antibody(s) antibody drug(s) antibody drug conjugate(s) (ADC) physicochemical properties pharmacokinetics monoclonal antibody(s) immunotherapy IgG antibody(s) drug design developability a b s t r a c t Antibody-based proteins have become an important class of biologic therapeutics, due in large part to the stability, specificity, and adaptability of the antibody framework. Indeed, antibodies not only have the inherent ability to bind both antigens and endogenous immune receptors but also have proven extremely amenable to protein engineering. Thus, several derivatives of the monoclonal antibody format, including bispecific antibodies, antibody-drug conjugates, and antibody fragments, have demonstrated efficacy for treating human disease, particularly in the fields of immunology and oncology. Reviewed here are considerations for the design of antibody-based therapeutics, including immunological context, therapeutic mechanisms, and engineering strategies. First, characteristics of antibodies are introduced, with emphasis on structural domains, functionally important receptors, isotypic and allotypic differences, and modifications such as glycosylation. Then, aspects of therapeutic antibody design are discussed, including identification of antigen-specific variable regions, choice of expression system, use of multispecific formats, and design of antibody derivatives based on fragmentation, oligomerization, or conjugation to other functional moieties. Finally, strategies to enhance antibody function through protein engineering are reviewed while highlighting the impact of fundamental biophysical properties on protein developability.

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Section: Charge and Isoelectric Pointmentioning

confidence: 99%

Section: Charge and Isoelectric Pointmentioning

confidence: 99%

Considerations for the Design of Antibody-Based Therapeutics

Goulet

Atkins

2020

Journal of Pharmaceutical Sciences

201

154

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“…FcRn-mediated recycling can be improved by engineering the Fc-FcRn binding properties, which has been shown to result in a reduced clearance and prolonged half-life in vivo. [11][12][13][14] Efficient FcRn-mediated antibody recycling relies on a delicate balance between binding at low endosomal pH and immediate release/ non-binding at serum pH. 15,16 Residual binding at serum pH may be a result of interactions between the constant or the variable antibody domains with FcRn.…”

Section: Introductionmentioning

confidence: 99%

Heparin chromatography as an in vitro predictor for antibody clearance rate through pinocytosis

Kraft

Richter

Emrich

et al. 2019

mAbs

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The pharmacokinetic (PK) properties of therapeutic antibodies directly affect efficacy, dose and dose intervals, application route and tissue penetration. In indications where health-care providers and patients can choose between several efficacious and safe therapeutic options, convenience (determined by dosing interval or route of application), which is mainly driven by PK properties, can affect drug selection. Therapeutic antibodies can have greatly different PK even if they have identical Fc domains and show no target-mediated drug disposition. Biophysical properties like surface charge or hydrophobicity, and binding to surrogates for high abundant off-targets (e.g., baculovirus particles, Chinese hamster ovary cell membrane proteins) were proposed to be responsible for these differences. Here, we used heparin chromatography to separate a polyclonal mix of endogenous human IgGs (IVIG) into fractions that differ in their PK properties. Heparin was chosen as a surrogate for highly negatively charged glycocalyx components on endothelial cells, which are among the main contributors to nonspecific clearance. By directly correlating heparin retention time with clearance, we identified heparin chromatography as a tool to assess differences in unspecific cell–surface interaction and the likelihood for increased pinocytotic uptake and degradation. Building on these results, we combined predictors for FcRn-mediated recycling and cell–surface interaction. The combination of heparin and FcRn chromatography allow identification of antibodies with abnormal PK by mimicking the major root causes for fast, non-target-mediated, clearance of therapeutic, Fc-containing proteins.

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“…In addition to the importance of charge in the development of high concentration therapeutic formulations, mAb charge may influence in vivo processes. For example, neonatal Fc receptor (FcRn)-independent clearance rates are lower for mAbs with lower pI values than those with higher pI values [16,17,18], presumably due to decreased nonspecific cell surface binding [16,17,19,20]. Furthermore, basic charge variants of mAbs display stronger binding to the FcγRIIIa receptor and increased antibody-dependent cellular cytotoxicity response compared to more acidic charge variants [21,22].…”

Section: Introductionmentioning

confidence: 99%

IgG Charge: Practical and Biological Implications

et al. 2019

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Practically, IgG charge can contribute significantly to thermodynamic nonideality, and hence to solubility and viscosity. Biologically, IgG charge isomers exhibit differences in clearance and potency. It has been known since the 1930s that all immunoglobulins carry a weak negative charge in physiological solvents. However, there has been no systematic exploration of this fundamental property. Accurate charge measurements have been made using membrane confined electrophoresis in two solvents (pH 5.0 and pH 7.4) on a panel of twelve mAb IgGs, as well as their F(ab’)2 and Fc fragments. The following observations were made at pH 5.0: (1) the measured charge differs from the calculated charge by ~40 for the intact IgGs, and by ~20 for the Fcs; (2) the intact IgG charge depends on both Fv and Fc sequences, but does not equal the sum of the F(ab)’2 and Fc charge; (3) the Fc charge is consistent within a class. In phosphate buffered saline, pH 7.4: (1) the intact IgG charges ranged from 0 to −13; (2) the F(ab’)2 fragments are nearly neutral for IgG1s and IgG2s, and about −5 for some of the IgG4s; (3) all Fc fragments are weakly anionic, with IgG1 < IgG2 < IgG4; (4) the charge on the intact IgGs does not equal the sum of the F(ab’)2 and Fc charge. In no case is the calculated charge, based solely on H+ binding, remotely close to the measured charge. Some mAbs carried a charge in physiological salt that was outside the range observed for serum-purified human poly IgG. To best match physiological properties, a therapeutic mAb should have a measured charge that falls within the range observed for serum-derived human IgGs. A thermodynamically rigorous, concentration-dependent protein–protein interaction parameter is introduced. Based on readily measured properties, interaction curves may be generated to aid in the selection of proteins and solvent conditions. Example curves are provided.

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Pharmacokinetic and Pharmacodynamic Considerations in the Design of Therapeutic Antibodies

Cited by 35 publications

References 112 publications

Considerations for the Design of Antibody-Based Therapeutics

Considerations for the Design of Antibody-Based Therapeutics

Heparin chromatography as an in vitro predictor for antibody clearance rate through pinocytosis

IgG Charge: Practical and Biological Implications

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