A Novel NAMPT Inhibitor-Based Antibody-Drug Conjugate Payload Class for Cancer Therapy

被引：16

作者：

Boehnke, Niels ^{[1
]}

Berger, Markus ^{[1
]}

Griebenow, Nils ^{[2
,3
]}

Rottmann, Antje ^{[1
]}

Erkelenz, Michael ^{[1
,4
]}

Hammer, Stefanie ^{[1
]}

Berndt, Sandra ^{[1
]}

Guenther, Judith ^{[1
]}

Wengner, Antje M. ^{[1
]}

Stelte-Ludwig, Beatrix ^{[5
]}

Mahlert, Christoph ^{[2
]}

Greven, Simone ^{[2
]}

Dietz, Lisa ^{[2
]}

Jorissen, Hannah ^{[2
]}

Barak, Naomi ^{[1
]}

Boemer, Ulf ^{[1
,4
]}

Hillig, Roman C. ^{[1
,4
]}

Eberspaecher, Uwe ^{[1
]}

Weiske, Jorg ^{[1
,4
]}

Giese, Anja ^{[1
]}

Mumberg, Dominik ^{[1
,6
]}

Nising, Carl Friedrich ^{[1
]}

Weinmann, Hilmar ^{[1
,7
]}

Sommer, Anette ^{[1
,8
]}

机构：

[1] Bayer AG, Pharmaceut, D-13353 Berlin, Germany

[2] Bayer AG, Pharmaceut, D-42113 Wuppertal, Germany

[3] Elanco Anim Hlth, Lead Discovery Chem, Discovery Res, Alfred Nobel Str 50, D-40789 Monheim, Germany

[4] Nuvisan ICB GmbH, Mullerstra 178, D-13342 Berlin, Germany

[5] Vincerx Pharma GmbH, Alfred Nobel Str 10, D-40789 Monheim, Germany

[6] Adcendo ApS, Ole Maaloees Vej 3, DK-2200 Copenhagen, Denmark

[7] Janssen Pharmaceut NV, Turnhoutseweg 30, B-2340 Beerse, Belgium

[8] Pfizer Worldwide Res, Dev & Med, Linkstr 10, D-10785 Berlin, Germany

来源：

BIOCONJUGATE CHEMISTRY | 2022年 / 33卷 / 06期

关键词：

NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE; LINKERS; POTENCY;

D O I：

10.1021/acs.bioconjchem.2c00178

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

Inhibition of intracellular nicotinamide phosphoribosyltransferase (NAMPT) represents a new mode of action for cancer-targeting antibody-drug conjugates (ADCs) with activity also in slowly proliferating cells. To extend the repertoire of available effector chemistries, we have developed a novel structural class of NAMPT inhibitors as ADC payloads. A structure-activity relationship-driven approach supported by protein structural information was pursued to identify a suitable attachment point for the linker to connect the NAMPT inhibitor with the antibody. Optimization of scaffolds and linker structures led to highly potent effector chemistries which were conjugated to antibodies targeting C4.4a (LYPD3), HER2 (c-erbB2), or B7H3 (CD276) and tested on antigen-positive and -negative cancer cell lines. Pharmacokinetic studies, including metabolite profiling, were performed to optimize the stability and selectivity of the ADCs and to evaluate potential bystander effects. Optimized NAMPTi-ADCs demonstrated potent in vivo antitumor efficacy in target antigen-expressing xenograft mouse models. This led to the development of highly potent NAMPT inhibitor ADCs with a very good selectivity profile compared with the corresponding isotype control ADCs. Moreover, we demonstrate-to our knowledge for the first time-the generation of NAMPTi payload metabolites from the NAMPTi-ADCs in vitro and in vivo. In conclusion, NAMPTi-ADCs represent an attractive new payload class designed for use in ADCs for the treatment of solid and hematological cancers.

引用

页码：1210 / 1221

页数：12

共 28 条

[1] Antibody-Drug Conjugates-A Tutorial Review [J].