Author: Nocito, Sandro ; Joly, Emilie ; Nieto-Oberhuber, Cristina M ; Richard, Etienne ; Lagasse-Guerro, Stephanie ; Lorenzana, Edward G ; Abrams, Tinya ; Rudewicz, Patrick J ; Mallet, William ; Schindler, Patrick ; Venstrom, Kristine ; Jones, Darryl ; Granda, Brian ; Zurini, Mauro ; Wang, Peiyin ; Dillon, Michael P ; Piizzi, Grazia ; Oei, Yoko ; Chamoin, Sylvie ; Lafrance, Marc ; Lacaud-Baumlin, Marion ; Daniel, Dylan ; Marzinzik, Andreas L ; Beng-Louka, Edwige ; Fedoseev, Pavel ; Perruccio, Francesca ; Drosos, Nikolaos ; Doumampouom-Metoul, Lionel ; Martyniuk, Piotr ; Blanco, Enrique ; Karpov, Alexei S ; Chene, Patrick ; Grotzfeld, Robert M ; Velay, Mélanie ; Dacquignies, Isabelle ; Furegati, Markus ; Mesrouze, Yannick ; Hess Clark, Suzanna

Targeted antimitotic agents are a promising class of anticancer therapies. Herein, we describe the development of a potent and selective antimitotic Eg5 inhibitor based antibody-drug conjugate (ADC). Preliminary studies were performed using proprietary Eg5 inhibitors which were conjugated onto a HER2-targeting antibody using maleimido caproyl valine-citrulline para-amino benzocarbamate, or MC-VC-PABC cleavable linker. However, the resulting ADCs lacked antigen-specificity in vivo, probably from premature release of the payload. Second-generation ADCs were then developed, using noncleavable linkers, and the resulting conjugates (ADC-4 and ADC-10) led to in vivo efficacy in an HER-2 expressing (SK-OV-3ip) mouse xenograft model while ADC-11 led to in vivo efficacy in an anti-c-KIT (NCI-H526) mouse xenograft model in a target-dependent manner.

09 Aug 2018·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Nicotinamide Phosphoribosyltransferase Inhibitor as a Novel Payload for Antibody–Drug Conjugates

Q3 · MEDICINE

Article

Author: Nieto-Oberhuber, Cristina M. ; Mohseni, Morvarid ; Gesner, Thomas G. ; Meredith, Erik ; Abrams, Tinya ; Karpov, Alexei S. ; Dillon, Michael P. ; Raikar, Ankita ; Martyniuk, Piotr ; D’Alessio, Joseph A. ; Zurini, Mauro ; Palacios, Daniel ; Mallet, William ; Clark, Suzanna ; Jones, Darryl ; Perruccio, Francesca ; Piizzi, Grazia ; Lacaud, Marion ; Bialucha, Carl Uli

Antibody-drug conjugates (ADCs) are a novel modality that allows targeted delivery of potent therapeutic agents to the desired site. Herein we report our discovery of NAMPT inhibitors as a novel nonantimitotic payload for ADCs. The resulting anti-c-Kit conjugates (ADC-3 and ADC-4) demonstrated in vivo efficacy in the c-Kit positive gastrointestinal stromal tumor GIST-T1 xenograft model in a target-dependent manner.

21 Feb 2018·Bioconjugate ChemistryQ2 · CHEMISTRY

Immolation of p-Aminobenzyl Ether Linker and Payload Potency and Stability Determine the Cell-Killing Activity of Antibody–Drug Conjugates with Phenol-Containing Payloads

Q2 · CHEMISTRY

Article

Author: Khojasteh, S. Cyrus ; Guo, Jun ; Vollmar, Breanna S. ; Vandlen, Richard ; Lewis Phillips, Gail D. ; Bobba, Sudheer ; Sadowsky, Jack D. ; Staben, Leanna ; Ma, Yong ; Zhang, Donglu ; Fan, Peter ; Pillow, Thomas H. ; Su, Dian ; Wei, BinQing ; Zhang, Chenghong ; Dragovich, Peter S. ; Le, Hoa ; Kozak, Katherine R. ; Hop, Cornelis E. C. A. ; Cruz-Chuh, Josefa dela

The valine-citrulline (Val-Cit) dipeptide and p-aminobenzyl (PAB) spacer have been commonly used as a cleavable self-immolating linker in ADC design including in the clinically approved ADC, brentuximab vedotin (Adcetris). When the same linker was used to connect to the phenol of the cyclopropabenzindolone (CBI) (P1), the resulting ADC1 showed loss of potency in CD22 target-expressing cancer cell lines (e.g., BJAB, WSU-DLCL2). In comparison, the conjugate (ADC2) of a cyclopropapyrroloindolone (CPI) (P2) was potent despite the two corresponding free drugs having similar picomolar cell-killing activity. Although the corresponding spirocyclization products of P1 and P2, responsible for DNA alkylation, are a prominent component in buffer, the linker immolation was slow when the PAB was connected as an ether (PABE) to the phenol in P1 compared to that in P2. Additional immolation studies with two other PABE-linked substituted phenol compounds showed that electron-withdrawing groups accelerated the immolation to release an acidic phenol-containing payload (to delocalize the negative charge on the anticipated anionic phenol oxygen during immolation). In contrast, efficient immolation of LD4 did not result in an active ADC4 because the payload (P4) had a low potency to kill cells. In addition, nonimmolation of LD5 did not affect the cell-killing potency of its ADC5 since immolation is not required for DNA alkylation by the center-linked pyrrolobenzodiazepine. Therefore, careful evaluation needs to be conducted when the Val-Cit-PAB linker is used to connect antibodies to a phenol-containing drug as the linker immolation, as well as payload potency and stability, affects the cell-killing activity of an ADC.

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Neoplasms	Preclinical	India	Zydus Cadila Healthcare Ltd.	-

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