Anti-CD30 diabody-drug conjugates with potent antitumor activity

Kim, Kristine M.; McDonagh, Charlotte F.; Westendorf, Lori; Brown, Lindsay L.; Sussman, Django; Feist, Tiffany; Lyon, Robert P.; Alley, Stephen C.; Okeley, Nicole M.; Zhang, Xinqun; Thompson, Melissa C.; Stone, Ivan J.; Gerber, Hans‐Peter; Carter, Paul J.

doi:10.1158/1535-7163.mct-08-0388

Cited by 84 publications

(66 citation statements)

References 36 publications

(68 reference statements)

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“…UV/vis spectroscopy is the most commonly implemented technique to determine DAR. This molar ratio can be derived from the Beer-Lambert law by comparing the IgG absorbance maxima at 280 nm to that of a drug molecule in simultaneous equations (34,67,(71)(72)(73)(74). ADCs with a variety of payloads have been evaluated using this method, including DM1, methotrexate, calicheamicin analogues, and auristatins (11,75,76).…”

Section: Uv/vismentioning

confidence: 99%

Antibody Drug Conjugates: Design and Selection of Linker, Payload and Conjugation Chemistry

McCombs

Owen

2015

AAPS J

266

190

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Abstract. Antibody drug conjugates (ADCs) have emerged as an important pharmaceutical class of drugs designed to harness the specificity of antibodies with the potency of small molecule therapeutics. The three main components of ADCs are the antibody, the linker, and the payload; the majority of early work focused intensely on improving the functionality of these pieces. Recently, considerable attention has been focused on developing methods to control the site and number of linker/drug conjugated to the antibody, with the aim of producing more homogenous ADCs. In this article, we review popular conjugation methods and highlight recent approaches including "click" conjugation and enzymatic ligation. We discuss current linker technology, contrasting the characteristics of cleavable and noncleavable linkers, and summarize the essential properties of ADC payload, centering on chemotherapeutics. In addition, we report on the progress in characterizing to determine physicochemical properties and on advances in purifying to obtain homogenous products. Establishing a set of selection and analytical criteria will facilitate the translation of novel ADCs and ensure the production of effective biosimilars.

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Section: Uv/vismentioning

confidence: 99%

Antibody Drug Conjugates: Design and Selection of Linker, Payload and Conjugation Chemistry

McCombs

Owen

2015

AAPS J

266

190

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“…As a case in point, preclinical studies with anti-CD30 diabodies conjugated to auristatin demonstrated efficacy in preclinical tumor models (83). However, whether such approaches yield improved tumor penetration and hence enhanced clinical responses in patients remains to be seen.…”

Section: Barriers To Effective Tumor Penetrationmentioning

confidence: 99%

Antibody Drug Conjugates: Preclinical Considerations

Bornstein

2015

AAPS J

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ABSTRACT. The development path for antibody drug conjugates (ADCs) is more complex and challenging than for unmodified antibodies. While many of the preclinical considerations for both unmodified and antibody drug conjugates are shared, special considerations must be taken into account when developing an ADC. Unlike unmodified antibodies, an ADC must preferentially bind to tumor cells, internalize, and traffic to the appropriate intracellular compartment to release the payload. Parameters that can impact the pharmacological properties of this class of therapeutics include the selection of the payload, the type of linker, and the methodology for payload drug conjugation. Despite a plethora of in vitro assays and in vivo models to screen and evaluate ADCs, the challenge remains to develop improved preclinical tools that will be more predictive of clinical outcome. This review will focus on preclinical considerations for clinically validated small molecule ADCs. In addition, the lessons learned from Mylotarg®, the first in class FDA-approved ADC, are highlighted.

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“…Tumor targeting by the anti-CD70 mAb h1F6 C4v2 showed substantial accumulation in CD70-positive tumor xenografts. The peak mAb concentration of 40.9 Ϯ 9.7% ID/g was achieved 1 day after dose, a very high value for tumor targeting by mAbs (Ferl et al, 2006;Cai et al, 2007;Kim et al, 2008;SmithJones et al, 2008). Serum drug-linker stability measurements indicate that about half the drug is lost from the ADC during the 10-day period, which is considerably longer than the circulating half-life of the conjugate.…”

Section: Discussionmentioning

confidence: 95%

The Pharmacologic Basis for Antibody-Auristatin Conjugate Activity

Alley¹,

Zhang²,

Okeley³

et al. 2009

J Pharmacol Exp Ther

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125

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Antibody-drug conjugates (ADCs) made with auristatin antimitotic agents have shown significant preclinical and clinical oncology activity. SGN-75 is composed of the anti-CD70 antibody h1F6 conjugated to monomethylauristatin F through a noncleavable maleimidocaproyl linkage. To understand the pharmacologic basis of the activity of this ADC, its pharmacokinetics and biodistribution were evaluated in a mouse xenograft model with use of a dual-radiolabeled ADC. The concentrations of antibody, total auristatin (conjugated plus unconjugated), and unconjugated auristatin were measured simultaneously in serum, tumor, and 16 normal tissues. Serum pharmacokinetic parameters for antibody and total auristatin were similar with very little unconjugated auristatin observed, demonstrating a high degree of stability. The kinetic values in normal tissues generally tracked with serum: the first time point (1 h) had the highest antibody and total auristatin concentrations with low unconjugated auristatin concentrations, with the exception of organs expected to be involved in hepatobiliary clearance of the ADC, where total and unconjugated auristatin concentrations peaked at 4 h and then rapidly decreased. In tumors, antibody concentrations were maximal at 1 day, with total auristatin increasing until 2 days. Intratumoral unconjugated auristatin was a substantial fraction of the total auristatin and reached concentrations much higher than in normal tissues. The exposure of the tumor to total and unconjugated auristatin was tens to hundreds times higher than normal tissue exposure. The data establish the pharmacologic basis of activity of the ADC through specific tumor targeting, intratumoral auristatin retention, and ADC stability in the systemic circulation.

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Anti-CD30 diabody-drug conjugates with potent antitumor activity

Cited by 84 publications

References 36 publications

Antibody Drug Conjugates: Design and Selection of Linker, Payload and Conjugation Chemistry

Antibody Drug Conjugates: Design and Selection of Linker, Payload and Conjugation Chemistry

Antibody Drug Conjugates: Preclinical Considerations

The Pharmacologic Basis for Antibody-Auristatin Conjugate Activity

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