2 research outputs found
Antibody–Drug Conjugates (ADCs) Derived from Interchain Cysteine Cross-Linking Demonstrate Improved Homogeneity and Other Pharmacological Properties over Conventional Heterogeneous ADCs
Conventional antibody–drug
conjugates (ADCs) are heterogeneous
mixtures of chemically distinct molecules that vary in both drugs/antibody
(DAR) and conjugation sites. Suboptimal properties of heterogeneous
ADCs have led to new site-specific conjugation methods for improving
ADC homogeneity. Most site-specific methods require extensive antibody
engineering to identify optimal conjugation sites and introduce unique
functional groups for conjugation with appropriately modified linkers.
Alternative nonrecombinant methods have emerged in which bifunctional
linkers are utilized to cross-link antibody interchain cysteines and
afford ADCs containing four drugs/antibody. Although these methods
have been shown to improve ADC homogeneity and stability in vitro,
their effect on the pharmacological properties of ADCs in vivo is
unknown. In order to determine the relative impact of interchain cysteine
cross-linking on the therapeutic window and other properties of ADCs
in vivo, we synthesized a derivative of the known ADC payload, MC-MMAF,
that contains a bifunctional dibromomaleimide (DBM) linker instead
of a conventional maleimide (MC) linker. The DBM-MMAF derivative was
conjugated to trastuzumab and a novel anti-CD98 antibody to afford
ADCs containing predominantly four drugs/antibody. The pharmacological
properties of the resulting cross-linked ADCs were compared with analogous
heterogeneous ADCs derived from conventional linkers. The results
demonstrate that DBM linkers can be applied directly to native antibodies,
without antibody engineering, to yield highly homogeneous ADCs via
cysteine cross-linking. The resulting ADCs demonstrate improved pharmacokinetics,
superior efficacy, and reduced toxicity in vivo compared to analogous
conventional heterogeneous ADCs
Discovery of (<i>R</i>)‑4-Cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro‑1<i>H</i>‑pyrazolo[4,3‑<i>c</i>]quinoline (ELND006) and (<i>R</i>)‑4-Cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro‑2<i>H</i>‑pyrazolo[4,3‑<i>c</i>]quinoline (ELND007): Metabolically Stable γ‑Secretase Inhibitors that Selectively Inhibit the Production of Amyloid‑β over Notch
Herein,
we describe our strategy to design metabolically stable γ-secretase
inhibitors which are selective for inhibition of Aβ generation
over Notch. We highlight our synthetic strategy to incorporate diversity
and chirality. Compounds <b>30</b> (ELND006) and <b>34</b> (ELND007) both entered human clinical trials. The in vitro and in
vivo characteristics for these two compounds are described. A comparison
of inhibition of Aβ generation in vivo between <b>30</b>, <b>34</b>, Semagacestat <b>41</b>, Begacestat <b>42</b>, and Avagacestat <b>43</b> in mice is made. <b>30</b> lowered Aβ in the CSF of healthy human volunteers