The Methylene Alkoxy Carbamate Self-Immolative Unit: Utilization for the Targeted Delivery of Alcohol-Containing Payloads with Antibody-Drug Conjugates

A strategy for the conjugation of alcohol‐containing payloads to antibodies has been developed and involves the methylene alkoxy carbamate (MAC) self‐immolative unit. A series of MAC β‐glucuronide model constructs were prepared to evaluate stability and enzymatic release, and the results demonstrate...

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Published in:	Angewandte Chemie International Edition Vol. 55; no. 28; pp. 7948 - 7951
Main Authors:	Kolakowski, Robert V., Haelsig, Karl T., Emmerton, Kim K., Leiske, Chris I., Miyamoto, Jamie B., Cochran, Julia H., Lyon, Robert P., Senter, Peter D., Jeffrey, Scott C.
Format:	Journal Article
Language:	English
Published:	Germany Blackwell Publishing Ltd 04-07-2016 Wiley Subscription Services, Inc
Edition:	International ed. in English
Subjects:	Alcohol Alcohols Antibodies cancer CD30 antigen Conjugates Conjugation Disruption drug delivery Drug delivery systems glycoconjugate Immunoglobulin G Methylene Payloads Physiology Stability analysis Technology assessment Utilization alcohols antibodies cancer drug delivery glycoconjugate
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Abstract	A strategy for the conjugation of alcohol‐containing payloads to antibodies has been developed and involves the methylene alkoxy carbamate (MAC) self‐immolative unit. A series of MAC β‐glucuronide model constructs were prepared to evaluate stability and enzymatic release, and the results demonstrated high stability at physiological pH in a substitution‐dependent manner. All the MAC model compounds efficiently released alcohol drug surrogates under the action of β‐glucuronidase. To assess the MAC technology for ADCs, the potent microtubule‐disrupting agent auristatin E (AE) was incorporated through the norephedrine alcohol. Conjugation of the MAC β‐glucuronide AE drug linker to the anti‐CD30 antibody cAC10, and an IgG control antibody, gave potent and immunologically specific activities in vitro and in vivo. These studies validate the MAC self‐immolative unit for alcohol‐containing payloads within ADCs, a class that has not been widely exploited. MAC out: A strategy for the conjugation of alcohol‐containing payloads to antibodies has been developed using the methylene alkoxy carbamate (MAC) self‐immolative unit. A series of MAC β‐glucuronide model constructs were prepared and demonstrated high stability at physiological pH, and efficiently released alcohol drug surrogates under the action of β‐glucuronidase.
AbstractList	A strategy for the conjugation of alcohol‐containing payloads to antibodies has been developed and involves the methylene alkoxy carbamate (MAC) self‐immolative unit. A series of MAC β‐glucuronide model constructs were prepared to evaluate stability and enzymatic release, and the results demonstrated high stability at physiological pH in a substitution‐dependent manner. All the MAC model compounds efficiently released alcohol drug surrogates under the action of β‐glucuronidase. To assess the MAC technology for ADCs, the potent microtubule‐disrupting agent auristatin E (AE) was incorporated through the norephedrine alcohol. Conjugation of the MAC β‐glucuronide AE drug linker to the anti‐CD30 antibody cAC10, and an IgG control antibody, gave potent and immunologically specific activities in vitro and in vivo. These studies validate the MAC self‐immolative unit for alcohol‐containing payloads within ADCs, a class that has not been widely exploited. MAC out: A strategy for the conjugation of alcohol‐containing payloads to antibodies has been developed using the methylene alkoxy carbamate (MAC) self‐immolative unit. A series of MAC β‐glucuronide model constructs were prepared and demonstrated high stability at physiological pH, and efficiently released alcohol drug surrogates under the action of β‐glucuronidase. A strategy for the conjugation of alcohol‐containing payloads to antibodies has been developed and involves the methylene alkoxy carbamate (MAC) self‐immolative unit. A series of MAC β‐glucuronide model constructs were prepared to evaluate stability and enzymatic release, and the results demonstrated high stability at physiological pH in a substitution‐dependent manner. All the MAC model compounds efficiently released alcohol drug surrogates under the action of β‐glucuronidase. To assess the MAC technology for ADCs, the potent microtubule‐disrupting agent auristatin E (AE) was incorporated through the norephedrine alcohol. Conjugation of the MAC β‐glucuronide AE drug linker to the anti‐CD30 antibody cAC10, and an IgG control antibody, gave potent and immunologically specific activities in vitro and in vivo. These studies validate the MAC self‐immolative unit for alcohol‐containing payloads within ADCs, a class that has not been widely exploited.
Author	Emmerton, Kim K. Lyon, Robert P. Haelsig, Karl T. Leiske, Chris I. Jeffrey, Scott C. Senter, Peter D. Kolakowski, Robert V. Cochran, Julia H. Miyamoto, Jamie B.
Author_xml	– sequence: 1 givenname: Robert V. surname: Kolakowski fullname: Kolakowski, Robert V. email: rkolakowski@seagen.com organization: Seattle Genetics, 21823 30th Dr SE, WA, 98021, Bothell, USA – sequence: 2 givenname: Karl T. surname: Haelsig fullname: Haelsig, Karl T. organization: Seattle Genetics, 21823 30th Dr SE, WA, 98021, Bothell, USA – sequence: 3 givenname: Kim K. surname: Emmerton fullname: Emmerton, Kim K. organization: Seattle Genetics, 21823 30th Dr SE, WA, 98021, Bothell, USA – sequence: 4 givenname: Chris I. surname: Leiske fullname: Leiske, Chris I. organization: Seattle Genetics, 21823 30th Dr SE, WA, 98021, Bothell, USA – sequence: 5 givenname: Jamie B. surname: Miyamoto fullname: Miyamoto, Jamie B. organization: Seattle Genetics, 21823 30th Dr SE, WA, 98021, Bothell, USA – sequence: 6 givenname: Julia H. surname: Cochran fullname: Cochran, Julia H. organization: Seattle Genetics, 21823 30th Dr SE, WA, 98021, Bothell, USA – sequence: 7 givenname: Robert P. surname: Lyon fullname: Lyon, Robert P. organization: Seattle Genetics, 21823 30th Dr SE, WA, 98021, Bothell, USA – sequence: 8 givenname: Peter D. surname: Senter fullname: Senter, Peter D. organization: Seattle Genetics, 21823 30th Dr SE, WA, 98021, Bothell, USA – sequence: 9 givenname: Scott C. surname: Jeffrey fullname: Jeffrey, Scott C. email: sjeffrey@seagen.com organization: Seattle Genetics, 21823 30th Dr SE, WA, 98021, Bothell, USA
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/27198854$$D View this record in MEDLINE/PubMed
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Snippet	A strategy for the conjugation of alcohol‐containing payloads to antibodies has been developed and involves the methylene alkoxy carbamate (MAC)... A strategy for the conjugation of alcohol-containing payloads to antibodies has been developed and involves the methylene alkoxy carbamate (MAC)...
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SubjectTerms	Alcohol Alcohols Antibodies cancer CD30 antigen Conjugates Conjugation Disruption drug delivery Drug delivery systems glycoconjugate Immunoglobulin G Methylene Payloads Physiology Stability analysis Technology assessment Utilization
Title	The Methylene Alkoxy Carbamate Self-Immolative Unit: Utilization for the Targeted Delivery of Alcohol-Containing Payloads with Antibody-Drug Conjugates
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