Tubulin Inhibitor-Based Antibody-Drug Conjugates for Cancer Therapy

Chen, Hao; Lin, Zongtao; Arnst, Kinsie E.; Miller, Duane D.; Li, Wei

doi:10.3390/molecules22081281

Cited by 165 publications

(145 citation statements)

References 151 publications

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“…The majority of ADCs currently under investigation utilize facilitated release of the payload via either chemical (low pHor thiol reducible) or enzymatic means (9,41). In our screening, we found that maximal potency and specificity of eribulin ADCs could be achieved when eribulin was paired with lysosomal enzyme-cleavable linkers, whereby the cathepsincleavable Val-Cit linkers showed better overall specificity than a legumain-cleavable Ala-Ala-Asn linker (42).…”

Section: Discussionmentioning

confidence: 84%

MORAb-202, an Antibody–Drug Conjugate Utilizing Humanized Anti-human FRα Farletuzumab and the Microtubule-targeting Agent Eribulin, has Potent Antitumor Activity

Cheng

Tanaka

et al. 2018

Molecular Cancer Therapeutics

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Microtubule-targeting agents (MTA) have been investigated for many years as payloads for antibody-drug conjugates (ADC). In many cases, these ADCs have shown limited benefits due to lack of efficacy or significant toxicity, which has spurred continued investigation into novel MTA payloads for next-generation ADCs. In this study, we have developed ADCs using the MTA eribulin, a derivative of the macrocyclic polyether natural product halichondrin B, as a payload. Eribulin ADCs demonstrated in vitro potency and specificity using various linkers and two different conjugation approaches. MORAb-202 is an investigational agent that consists of the humanized anti-human folate receptor alpha (FRA) antibody farletuzumab conjugated via reduced interchain disulfide bonds to maleimido-PEG 2 -valine-citrulline-p-aminobenzylcarbamyl-eribulin at a drug-to-antibody ratio of 4.0. MORAb-202 displayed preferable biophysical properties and broad potency across a number of FRA-positive tumor cell lines as well as demonstrated improved specificity in vitro compared with farletuzumab conjugated with a number of other MTA payloads, including MMAE, MMAF, and the reducible maytansine linker-payload sulfo-SPDB-DM4. A single-dose administration of MORAb-202 in FRA-positive human tumor cell line xenograft and patient-derived tumor xenograft models elicited a robust and durable antitumor response. These data support further investigation of MORAb-202 as a potential new treatment modality for FRA-positive cancers, using the novel MTA eribulin as a payload. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

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Section: Discussionmentioning

confidence: 84%

MORAb-202, an Antibody–Drug Conjugate Utilizing Humanized Anti-human FRα Farletuzumab and the Microtubule-targeting Agent Eribulin, has Potent Antitumor Activity

Cheng

Tanaka

et al. 2018

Molecular Cancer Therapeutics

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“…19) led by the recent Biologics License Application filing for polatuzumab vedotin (CD79b targeted) in relapsed/refractory diffuse large B-cell lymphoma. Although ADCs have not yet delivered on the promise of a moretargeted chemotherapy with an improved toxicity profile, new strategies may prove crucial to improving the therapeutic index of ADCs (4,20,21). These strategies include the use of warheads with lower potencies and alternative mechanisms of activity as described below.…”

Section: Overview Of Adcs In Clinical Developmentmentioning

confidence: 99%

Antibody–Drug Conjugates: Future Directions in Clinical and Translational Strategies to Improve the Therapeutic Index

Coats

Williams

Kebble

et al. 2019

Clinical Cancer Research

242

171

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Since the first approval of gemtuzumab ozogamicin (Mylotarg; Pfizer; CD33 targeted), two additional antibodydrug conjugates (ADC), brentuximab vedotin (Adcetris; Seattle Genetics, Inc.; CD30 targeted) and inotuzumab ozogamicin (Besponsa; Pfizer; CD22 targeted), have been approved for hematologic cancers and 1 ADC, trastuzumab emtansine (Kadcyla; Genentech; HER2 targeted), has been approved to treat breast cancer. Despite a clear clinical benefit being demonstrated for all 4 approved ADCs, the toxicity profiles are comparable with those of standard-of-care chemotherapeutics, with dose-limiting toxicities associated with the mecha-nism of activity of the cytotoxic warhead. However, the enthusiasm to develop ADCs has not been dampened; approximately 80 ADCs are in clinical development in nearly 600 clinical trials, and 2 to 3 novel ADCs are likely to be approved within the next few years. While the promise of a more targeted chemotherapy with less toxicity has not yet been realized with ADCs, improvements in technology combined with a wealth of clinical data are helping to shape the future development of ADCs. In this review, we discuss the clinical and translational strategies associated with improving the therapeutic index for ADCs.

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“…In addition, the discovery of tubulin inhibitors with different inhibition mechanisms (such as targeting two pathways with one compound) will open alternative avenues to bypass the problem of drug resistance. Another strategy involves utilizing antibody‐drug conjugates of tubulin inhibitors for targeted drug delivery to circumvent MDR, improve the therapeutic window, and limit toxicities . While significant strides have been made to address MDR, resistance is often multifactorial and heterogeneous.…”

Section: Mechanisms Of Multidrug Resistancementioning

confidence: 99%

“…Another strategy involves utilizing antibody-drug conjugates of tubulin inhibitors for targeted drug delivery to circumvent MDR, improve the therapeutic window, and limit toxicities. 130 While significant strides have been made to address MDR, resistance is often multifactorial and heterogeneous. Therefore, efforts to gain insight into tumor dependence and the relationship of the individual drug resistance effectors may assist in combating the complex phenomenon of MDR.…”

mentioning

confidence: 99%

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

Arnst

Banerjee

Chen

et al. 2019

Medicinal Research Reviews

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122

107

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Microtubule (MT)‐targeting agents are highly successful drugs as chemotherapeutic agents, and this is attributed to their ability to target MT dynamics and interfere with critical cellular functions, including, mitosis, cell signaling, intracellular trafficking, and angiogenesis. Because MT dynamics vary in the different stages of the cell cycle, these drugs tend to be the most effective against mitotic cells. While this class of drug has proven to be effective against many cancer types, significant hurdles still exist and include overcoming aspects such as dose limited toxicities and the development of resistance. Newer generations of developed drugs attack these problems and alternative approaches such as the development of dual tubulin and kinase inhibitors are being investigated. This approach offers the potential to show increased efficacy and lower toxicities. This review covers different categories of MT‐targeting agents, recent advances in dual inhibitors, and current challenges for this drug target.

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Tubulin Inhibitor-Based Antibody-Drug Conjugates for Cancer Therapy

Cited by 165 publications

References 151 publications

MORAb-202, an Antibody–Drug Conjugate Utilizing Humanized Anti-human FRα Farletuzumab and the Microtubule-targeting Agent Eribulin, has Potent Antitumor Activity

MORAb-202, an Antibody–Drug Conjugate Utilizing Humanized Anti-human FRα Farletuzumab and the Microtubule-targeting Agent Eribulin, has Potent Antitumor Activity

Antibody–Drug Conjugates: Future Directions in Clinical and Translational Strategies to Improve the Therapeutic Index

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

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