Antibody-drug conjugates- stability and formulation

Duerr, Corinna; Frieß, Wolfgang

doi:10.1016/j.ejpb.2019.03.021

Cited by 48 publications

(30 citation statements)

References 125 publications

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“…86 Marketed ADCs are currently formulated at a relatively low concentration of 5-20 mg/mL and diluted for its IV injection to concentrations of 0.009-1.008 mg/ mL. 87 As mentioned earlier, mAbs are hydrophilic by nature and therefore normally have a high colloidal solution capacity. However, the introduction of hydrophobic payload linker systems could reduce the maximal capacity of mAb colloidal solutions drastically, which can result even in complete protein precipitation.…”

Section: Solubility and Capacity Of Colloidal Suspensionsmentioning

confidence: 99%

Alteration of Physicochemical Properties for Antibody-Drug Conjugates and Their Impact on Stability

Buecheler

Winzer

Weber

et al. 2020

Journal of Pharmaceutical Sciences

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a b s t r a c tAntibody conjugates, in particular antibody-drug conjugates (ADCs), are a fast-growing area in research and in the pharmaceutical industry. The covalent attachment of an antibody to a chemical moiety can be an effective measure for drug targeting or can also positively impact pharmacokinetics of small molecular compounds by serum half-life extension. Stability, physicochemical properties, and degradation pathways of biotherapeutics or small molecule therapeutics are often not totally known and understood. However, ADCs represent a hybrid of small molecular and macromolecular components, and their properties are still not fully understood and described. This review discusses the alteration of the physicochemical properties of antibodies upon conjugation of chemical moieties to its surface and the resulting impact on ADC stability.

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Section: Solubility and Capacity Of Colloidal Suspensionsmentioning

confidence: 99%

Alteration of Physicochemical Properties for Antibody-Drug Conjugates and Their Impact on Stability

Buecheler

Winzer

Weber

et al. 2020

Journal of Pharmaceutical Sciences

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“…It is well-documented that the addition of a small molecule drug to an otherwise soluble and stable antibody can cause aggregation and other physicochemical instability in the ADC [162,163]. This is not only because many of the small molecule drugs are bulky and hydrophobic in nature leading to a significant increase in the hydrophobicity of the ADC, but also because the conjugation can induce perturbations to secondary and tertiary structures of the antibody resulting in reduced conformational stabilities.…”

Section: Conjugate Developability Formulations and Characteristicsmentioning

confidence: 99%

“…In addition to all the issues encountered during antibody formulation development, the formulation development of ADC drugs must find suitable pH and excipient conditions to simultaneously maintain the stability of the antibody, the linker, and the small molecule drug (reviewed in [162,163]). Even if there is an in-depth understanding of the stability of the parental antibody in aqueous solution, its physical stability may change upon conjugation in the presence of organic solvent or through possible cross-linking mechanism, and its chemical stability may depend on the conjugation method [178].…”

Section: Conjugate Developability Formulations and Characteristicsmentioning

confidence: 99%

Antibody Conjugates-Recent Advances and Future Innovations

et al. 2020

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Monoclonal antibodies have evolved from research tools to powerful therapeutics in the past 30 years. Clinical success rates of antibodies have exceeded expectations, resulting in heavy investment in biologics discovery and development in addition to traditional small molecules across the industry. However, protein therapeutics cannot drug targets intracellularly and are limited to soluble and cell-surface antigens. Tremendous strides have been made in antibody discovery, protein engineering, formulation, and delivery devices. These advances continue to push the boundaries of biologics to enable antibody conjugates to take advantage of the target specificity and long half-life from an antibody, while delivering highly potent small molecule drugs. While the “magic bullet” concept produced the first wave of antibody conjugates, these entities were met with limited clinical success. This review summarizes the advances and challenges in the field to date with emphasis on antibody conjugation, linker-payload chemistry, novel payload classes, absorption, distribution, metabolism, and excretion (ADME), and product developability. We discuss lessons learned in the development of oncology antibody conjugates and look towards future innovations enabling other therapeutic indications.

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“…Antibody-drug conjugates (ADCs) represent a significant advance in oncology therapy, particularly in hematologic malignancies [1,2]. ADCs are immunoconjugates comprised of an engineered monoclonal antibody (mAb) that is chemically attached to a cytotoxic drug (or payload) via a stable chemical linker [1,[3][4][5]. The antibody targets of ADCs are carefully selected for specific cells of interest, such as tumor cells of a particular lineage [6].…”

Section: Introductionmentioning

confidence: 99%

“…The antibody targets of ADCs are carefully selected for specific cells of interest, such as tumor cells of a particular lineage [6]. The major therapeutic advantage of ADCs is their ability to selectively deliver a potent cytotoxic agent to target cancer cells, thereby minimizing off-target effects [3,4,7,8]. The cytotoxic payload is released into target cancer cells only after internalization of the intact ADC, for example, via receptor-mediated endocytosis and trafficking to the lysosome, where the linker is subsequently cleaved by protein degradation [2,6].…”

Section: Introductionmentioning

confidence: 99%

Antibody–drug conjugates for previously treated aggressive lymphomas: focus on polatuzumab vedotin

Burke

Morschhauser

Andorsky

et al. 2020

Expert Review of Clinical Pharmacology

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Introduction: Antibody-drug conjugates (ADCs) are immunoconjugates and comprise a monoclonal antibody that is chemically attached to a cytotoxic drug (or payload) via a stable chemical linker. Since the approval of the first ADC in 2000, there are now nine different approved agents and over 100 ADCs in the drug-development pipeline. Areas covered: This review briefly describes the ADCs approved for treatment of lymphoma and their distinguishing factors in terms of target, linker and payload. The clinical implications of the use of ADCs are also considered. Here, we focus on polatuzumab vedotin, an ADC targeted to CD79b, which is approved for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) who have received at least one (EU approval) or two (US approval) prior therapies and are not eligible for bone marrow transplantation. The characteristics of polatuzumab vedotin are discussed and clinical data are presented. The future of polatuzumab vedotin clinical development, and ADCs in general, are also considered. Expert opinion: ADCs represent a significant advance in the treatment of lymphoma. Polatuzumab vedotin has shown clinical efficacy and a tolerable safety profile in both first-line and R/R DLBCL; future studies are planned to further investigate this ADC.

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Antibody-drug conjugates- stability and formulation

Cited by 48 publications

References 125 publications

Alteration of Physicochemical Properties for Antibody-Drug Conjugates and Their Impact on Stability

Alteration of Physicochemical Properties for Antibody-Drug Conjugates and Their Impact on Stability

Antibody Conjugates-Recent Advances and Future Innovations

Antibody–drug conjugates for previously treated aggressive lymphomas: focus on polatuzumab vedotin

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