Sulfatase-cleavable linkers for antibody-drug conjugates

Bargh, Jonathan D; Walsh, Stephen J.; Isidro‐Llobet, Albert; Omarjee, Soleilmane; Carroll, Jason S.; Spring, David R.

doi:10.1039/c9sc06410a

Cited by 51 publications

(60 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hemiasterlin exhibited sub‐nanomolar cytotoxicity against all cell lines, whilst the potency of taltobulin was approximately one order of magnitude lower [9] . Pleasingly, both ADC 1 and ADC 2 displayed exquisite cytotoxicity against SKBR3 and BT474 cells, comparable to that reported for an analogous cathepsin‐cleavable trastuzumab–MMAE ADC (Table S5) [44, 49] . Furthermore, both ADCs had negligible activity against MCF7 cells at the concentrations tested.…”

Section: Figurementioning

confidence: 58%

Expeditious Total Synthesis of Hemiasterlin through a Convergent Multicomponent Strategy and Its Use in Targeted Cancer Therapeutics

et al. 2020

Self Cite

View full text Add to dashboard Cite

Hemiasterlin is an antimitotic marine natural product with reported sub-nanomolar potency against several cancer cell lines. Herein, we describe an expeditious total synthesis of hemiasterlin featuring a four-component Ugi reaction (Ugi-4CR) as the key step. The convergent synthetic strategy enabled rapid access to taltobulin (HTI-286), a similarly potent synthetic analogue. This short synthetic sequence enabled investigation of both hemiasterlin and taltobulin as cytotoxic payloads in antibody-drug conjugates (ADCs). These novel ADCs displayed sub-nanomolar cytotoxicity against HER2-expressing cancer cells, while showing no activity against antigen-negative cells. This study demonstrates an improved synthetic route to a highly valuable natural product, facilitating further investigation of hemiasterlin and its analogues as potential payloads in targeted therapeutics.

show abstract

Section: Figurementioning

confidence: 58%

Expeditious Total Synthesis of Hemiasterlin through a Convergent Multicomponent Strategy and Its Use in Targeted Cancer Therapeutics

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…This approach was used for the synthesis of several trastuzumab-based DAR 4 ADCs containing cathepsincleavable, sulfatase-cleavable, or non-cleavable spacers and an MMAE, hemiasterlin or doxorubicin payload. 25,154,155 In all cases 490% conversion to the desired DAR 4 species was observed, which existed as mixtures of full and half-antibody formats. The conjugates displayed complete stability in human plasma over 14 days and were highly potent and selective in vitro.…”

Section: Disulfide Rebridgingmentioning

confidence: 97%

“…low pH 17 or glutathione 18,19 ) or enzyme-(e.g. protease, 20 phosphatase, 21,22 glycosidase 23,24 or sulfatase 25 ) sensitive trigger is incorporated. 26 Cleavable linker technology therefore enables the selective release of an unmodified payload at the target cell.…”

Section: Introductionmentioning

confidence: 99%

Site-selective modification strategies in antibody–drug conjugates

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Approaches have included using peptide sequences that act as more selective protease substrates [9][10][11][12] , as well as exploiting alternative enzyme classes as release mechanisms. 13,14 We began with the hypothesis that a linker requiring tandem enzymatic cleavage events, where the second cleavage is hindered until the first cleavage occurs, would limit payload loss during circulation and reduce off-target toxicities. We were inspired by prodrug approaches employing hydrophilic glucuronide moieties, 4,15 and by glucuronide-containing cleavable linkers (Figure1B), 5,13 both of which are responsive toglucuronidase, a lysosomal enzyme that is often upregulated in malignant cells.…”

Section: Introductionmentioning

confidence: 99%

Tandem-Cleavage Linkers Improve the In Vivo Stability and Tolerability of Antibody-Drug Conjugates

Chuprakov

Ogunkoya

Barfield

et al. 2021

Preprint

View full text Add to dashboard Cite

Although peptide motifs represent the majority of cleavable linkers used in clinical-stage antibody-drug conjugates (ADCs), the sequences are often sensitive to cleavage by extracellular enzymes, such as elastase, leading to systemic release of the cytotoxic payload. This action reduces the therapeutic index by causing off-target toxicities that can be dose-limiting. For example, a common side-effect of ADCs made using peptide-cleavable linkers is myelosuppression, including neutropenia. Only a few reports describe methods for optimizing peptide linkers to maintain efficient and potent tumor payload delivery while enhancing circulating stability. Herein, we address these critical limitations through the development of a tandem-cleavage linker strategy, where two sequential enzymatic cleavage events mediate payload release. We prepared dipeptides that are protected from degradation in the circulation by a sterically-encumbering glucuronide moiety. Upon ADC internalization and lysosomal degradation, the monosaccharide is removed and the exposed dipeptide is degraded, liberating the attached payload inside the target cell. We used CD79b-targeted monomethyl auristatin E (MMAE) conjugates as our model system, and compared the stability, efficacy, and tolerability of ADCs made with tandem-cleavage linkers to ADCs made using standard technology with the vedotin linker. The results—where rat studies showed dramatically improved tolerability in the hematopoietic compartment—highlight the role that linker stability plays in efficacy and tolerability, and offer a means of improving an ADC’s therapeutic index for improved patient outcomes.

show abstract

Sulfatase-cleavable linkers for antibody-drug conjugates

Abstract: Arylsulfate-containing linkers are cleaved by lysosomal sulfatases to release payloads from ADCs at targeted cancer cells.

Cited by 51 publications

References 31 publications

Expeditious Total Synthesis of Hemiasterlin through a Convergent Multicomponent Strategy and Its Use in Targeted Cancer Therapeutics

Expeditious Total Synthesis of Hemiasterlin through a Convergent Multicomponent Strategy and Its Use in Targeted Cancer Therapeutics

Site-selective modification strategies in antibody–drug conjugates

Tandem-Cleavage Linkers Improve the In Vivo Stability and Tolerability of Antibody-Drug Conjugates

Contact Info

Product

Resources

About