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Review
. 2023 Aug 29;26(10):107778.
doi: 10.1016/j.isci.2023.107778. eCollection 2023 Oct 20.

Peripheral neuropathy associated with monomethyl auristatin E-based antibody-drug conjugates

Zhiwen Fu  1   2 , Chen Gao  1   2 , Tingting Wu  1   2 , Lulu Wang  1   2 , Shijun Li  1   2 , Yu Zhang  1   2 , Chen Shi  1   2
Affiliations
Review

Peripheral neuropathy associated with monomethyl auristatin E-based antibody-drug conjugates

Zhiwen Fu et al. iScience. .

Abstract

Since the successful approval of gemtuzumab ozogamicin, antibody-drug conjugates (ADCs) have emerged as a pivotal category of targeted therapies for cancer. Among these ADCs, the use of monomethyl auristatin E (MMAE) as a payload is prevalent in the development of ADC drugs, which has significantly improved overall therapeutic efficacy against various malignancies. However, increasing clinical observations have raised concerns regarding the potential nervous system toxicity associated with MMAE-based ADCs. Specifically, a higher incidence of peripheral neuropathy has been reported in ADCs incorporating MMAE as payloads. Considering the increasing global use of MMAE-based ADCs, it is imperative to provide an inclusive overview of diagnostic and management strategies for this adverse event. In this review, we examine current information and what future research directions are required to better understand and manage this type of clinical challenge.

Keywords: Cancer; Cancer systems biology; Health sciences; Medicine; Oncology; Toxicology.

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Conflict of interest statement

The authors declare no competing interests.

Figures

None
Graphical abstract
Figure 1
Figure 1
The risk differece of peripheral neuropathy among approved antibody-drug conjugates The mean incidences of peripheral neuropathy of any grade by payloads (A) and linkers (B).
Figure 2
Figure 2
Possible mechanisms underlying peripheral neuropathy associated with MMAE-based antibody-drug conjugates (ADCs) (A) target-dependent uptake of the ADCs. (B) the non-specific uptake of ADCs by healthy cells. (C) the premature MMAE release during circulation. (D) the bystander effects of MMAE-based ADCs. Once the MMAE is taken up in the peripheral nerve cells through the direct method (free MMAE) or the indirect method (MMAE-based ADC uptake to release MMAE), MMAE binds to abundant binding sites along the length of microtubules and disrupts the microtubules network, resulting in the onset of peripheral neuropath. In addition, in cases where nerve injury is caused by microtubule-targeting drugs, Schwann cells become activated and produce damage-associated molecular patterns (DAMPs), which in turn attract circulating leukocytes, such as M1-like macrophages, to the site of injury. It promotes the release of various pro-inflammatory cytokines, including IL-1β, TNFα, CXCL1, CXCL12, etc. These cytokines trigger neuroinflammation and convey nociceptive information to DRG neurons, leading to the perception of pain. The Figures were created with BioRender.com.
Figure 3
Figure 3
Chemical structure of MMAE-based antibody-drug conjugates (ADCs) The mc-vc-PABC cleavable linker is employed for the conjugation between payload and antibody, which comprised of a thiol-reactive maleimidocaproyl (mc) group, a valine-citrulline (vc) dipeptide, and a para-amino benzyloxycarbonyl (PABC) spacer. Vedotin, the mc-vc-PABC-MMAE drug/linker complex, undergoes the protease cleavage of valine-citrulline dipeptide linker by cathepsin B followed spontaneous elimination of PABC to release cytotoxin MMAE in its native form.
Figure 4
Figure 4
Diagnostic flowchart for peripheral neuropathy associated with MMAE-based antibody-drug conjugates (ADCs)
See this image and copyright information in PMC

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References

    1. Fu Z., Li S., Han S., Shi C., Zhang Y. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Transduct. Targeted Ther. 2022;7:93. - PMC - PubMed
    1. Akaiwa M., Dugal-Tessier J., Mendelsohn B.A. Antibody-drug conjugate payloads; study of auristatin derivatives. Chem. Pharm. Bull. 2020;68:201–211. - PubMed
    1. Chang H.P., Cheung Y.K., Shah D.K. Whole-body pharmacokinetics and physiologically based pharmacokinetic model for monomethyl auristatin E (MMAE) J. Clin. Med. 2021;10:1332. - PMC - PubMed
    1. Bartlett N.L., Sharman J.P., Oki Y., Advani R.H., Bello C.M., Winter J.N., Yang Y., Kennedy D.A., Jacobsen E.D. A phase 2 study of brentuximab vedotin in patients with relapsed or refractory CD30-positive non-Hodgkin lymphomas: interim results in patients with DLBCL and other B-cell lymphomas. Blood. 2013;122:848.
    1. Pro B., Advani R.H., Brice P., Bartlett N.L., Rosenblatt J.D., Illidge T., Matous J., Ramchandren R., Fanale M.A., Connors J.M., et al. Three-year survival results from an ongoing phase 2 study of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma. Blood. 2013;122:1809. - PMC - PubMed

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