Antibody–drug conjugates: current status and future directions

Perez, Heidi L.; Cardarelli, Pina M.; Deshpande, Shrikant; Gangwar, Sanjeev; Schroeder, G.; Vite, Gregory D.; Borzilleri, R. M.

doi:10.1016/j.drudis.2013.11.004

Cited by 380 publications

(302 citation statements)

References 104 publications

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“…Current-generation linkers are classified as either cleavable or noncleavable (45). The majority of cleavable linkers are designed to be selectively cleaved by enzymes in a low-pH environment such as a lysosome (47). This approach has been clinically validated by Adcetris®, which uses a cleavable dipeptide linker that undergoes cathepsin B cleavage within the lysosome (48).…”

Section: Stabilitymentioning

confidence: 99%

Antibody Drug Conjugates: Nonclinical Safety Considerations

Hinrichs

Dixit

2015

AAPS J

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Abstract. Antibody drug conjugates (ADCs) are biopharmaceutical molecules consisting of a cytotoxic small molecule covalently linked to a targeted protein carrier via a stable cleavable or noncleavable linker. The process of conjugation yields a highly complex molecule with biochemical properties that are distinct from those of the unconjugated components. The impact of these biochemical differences on the safety and pharmacokinetic (PK) profile of the conjugate must be considered when determining the types of nonclinical safety studies required to support clinical development of ADCs. The hybrid nature of ADCs highlights the need for a science-based approach to safety assessment that incorporates relevant aspects of small and large molecule testing paradigms. This thinking is reflected in current regulatory guidelines, where sections pertaining to conjugates allow for a flexible approach to nonclinical safety testing. The aim of this article is to review regulatory expectations regarding early assessment of nonclinical safety considerations and discuss how recent advances in our understanding of ADCmediated toxicity can be used to guide the types of nonclinical safety studies needed to support ADC clinical development. The review will also explore nonclinical testing strategies that can be used to streamline ADC development by assessing the safety and efficacy of next generation ADC constructs using a rodent screen approach.

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Section: Stabilitymentioning

confidence: 99%

Antibody Drug Conjugates: Nonclinical Safety Considerations

Hinrichs

Dixit

2015

AAPS J

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“…The concept of a "magic bullet" delivering a potent chemotherapeutic to cancer cells and not normal healthy cells was first proposed over a century ago (142). Today, standard of care oncology practice utilizes antibody-drug conjugates with the approval of trastuzumab-emtansine (TDM1) (143) and brentuxumab vedotin (144)(145)(146).…”

Section: Antibody-drug Conjugatesmentioning

confidence: 99%

Novel systemic therapy against malignant pleural mesothelioma

Mancuso

Neal

2017

Transl. Lung Cancer Res.

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Malignant pleural mesothelioma is an aggressive tumor of the pleura with an overall poor prognosis. Even with surgical resection, for which only a subset of patients are eligible, long term disease free survival is rare. Standard first-line systemic treatment consists of a platinum analog, an anti-metabolite, and sometimes anti-angiogenic therapy, but there is currently no well-established standard therapy for refractory or relapsed disease. This review focuses on efforts to develop improved systemic therapy for the treatment of malignant pleural mesothelioma (MPM) including cytotoxic systemic therapy, a variety of tyrosine kinase inhibitors and their downstream effector pathways, pharmacologic targeting of the epigenome, novel approaches to target proteins expressed on mesothelioma cells (such as mesothelin), arginine depletion therapy, and the emerging role of immunotherapy. Overall, these studies demonstrate the challenges of improving systemic therapy for MPM and highlight the need to develop therapeutic strategies to control this disease.

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“…13-15 For newer generation ADCs, advances in conjugation technologies have reduced the rates of payload loss by improving linker stability compared to the first-generation ADCs. 16-19 Moreover, understanding the effect of the site of conjugation, drug loading, and drug-linker design on ADC PK has enabled mitigation of accelerated clearance observed with some ADCs. 20-22 Mechanistic PK/pharmacodynamic (PD) 23-26 and multi-scale models 13-15 have been proposed to improve translatability from preclinical species to the clinic.…”

Section: Introductionmentioning

confidence: 99%

Prediction of non-linear pharmacokinetics in humans of an antibody-drug conjugate (ADC) when evaluation of higher doses in animals is limited by tolerability: Case study with an anti-CD33 ADC

Figueroa

Leipold

Leong

et al. 2018

mAbs

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For antibody-drug conjugates (ADCs) that carry a cytotoxic drug, doses that can be administered in preclinical studies are typically limited by tolerability, leading to a narrow dose range that can be tested. For molecules with non-linear pharmacokinetics (PK), this limited dose range may be insufficient to fully characterize the PK of the ADC and limits translation to humans. Mathematical PK models are frequently used for molecule selection during preclinical drug development and for translational predictions to guide clinical study design. Here, we present a practical approach that uses limited PK and receptor occupancy (RO) data of the corresponding unconjugated antibody to predict ADC PK when conjugation does not alter the non-specific clearance or the antibody-target interaction. We used a 2-compartment model incorporating non-specific and specific (target mediated) clearances, where the latter is a function of RO, to describe the PK of anti-CD33 ADC with dose-limiting neutropenia in cynomolgus monkeys. We tested our model by comparing PK predictions based on the unconjugated antibody to observed ADC PK data that was not utilized for model development. Prospective prediction of human PK was performed by incorporating in vitro binding affinity differences between species for varying levels of CD33 target expression. Additionally, this approach was used to predict human PK of other previously tested anti-CD33 molecules with published clinical data. The findings showed that, for a cytotoxic ADC with non-linear PK and limited preclinical PK data, incorporating RO in the PK model and using data from the corresponding unconjugated antibody at higher doses allowed the identification of parameters to characterize monkey PK and enabled human PK predictions.

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Antibody–drug conjugates: current status and future directions

Cited by 380 publications

References 104 publications

Antibody Drug Conjugates: Nonclinical Safety Considerations

Antibody Drug Conjugates: Nonclinical Safety Considerations

Novel systemic therapy against malignant pleural mesothelioma

Prediction of non-linear pharmacokinetics in humans of an antibody-drug conjugate (ADC) when evaluation of higher doses in animals is limited by tolerability: Case study with an anti-CD33 ADC

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