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Understanding the chemistry & pharmacology of antibody–drug conjugates in triple-negative breast cancer with special reference to exatecan derivatives

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Abstract

In the spectrum of breast malignancies, triple-negative breast cancer is the most widely spreading subtype of breast cancer due to a low availability of therapeutic remedies. Recently, antibody–drug conjugates dramatically resolved the landscape for the treatment of triple-negative breast cancer. This review mainly focuses on the chemistry, structure, mechanism of action, and role of antibody–drug conjugates in triple-negative breast cancer. Datopotecan Deruxtecan (Dato-DXd) is a new-generation ADC showing encouraging results for TNBC. In this review, we have also emphasized TROP-2-directed Datopotamab deruxtecan ADCs to treat triple-negative breast cancer, its synthesis, mechanism of action, pharmacokinetics, pharmacodynamics, adverse events, and their ongoing clinical trials.

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Data availability

No datasets were generated or analyzed during the current study.

Abbreviations

ADCs:

Antibody–drug conjugates

AML:

Acute myeloid leukemia

mAbs:

Monoclonal antibodies

GO:

Gemtuzumab ozogamicin

AEs:

Adverse events

OS:

Overall survival

BSC:

Best supportive care

MMAE:

Monomethyl auristatin E

HL:

Hodgkin lymphoma

ALCL:

Anaplastic large cell lymphoma

MF:

Mycosis fungoides

C-ALCL:

Cutaneous anaplastic large cell lymphoma

PTCL:

Peripheral T-cell lymphomas

ORR:

Objective response rate

PFS:

Progression-free survival

CR:

Complete response

T-DM1:

Trastuzumab emtansine DM1 emtansine

UC:

Urothelial carcinoma

InO:

Inotuzumab ozogamicin

ALL:

Acute lymphoblastic leukemia

SoC:

Standard-of-care

MP:

Moxetumomab pasudotox

HCL:

Hairy cell leukemia

PV:

Polatuzumab vedotin

DLBCL:

Diffuse large B-cell lymphoma

NHL:

Non-Hodgkin lymphoma

LBCL:

Large B cell lymphoma

EV:

Enfortumab vedotin

la/mUC:

Locally advanced or metastatic urothelial

QOL:

Quality of life

BPI-SF:

Brief Pain Inventory Short Form

T-DXd:

Trastuzumab deruxtecan

SG:

Sacituzumab govitecan

Trop-2:

Trophoblast cell surface antigen 2

TNBC:

Triple-negative breast cancer

CRC:

Colorectal cancer

SCLC:

Small cell lung cancer

GC:

Gastric cancer

ICIs:

Immune checkpoint inhibitors

TRAEs:

Treatment-related adverse events

RC48:

Disitamab vedotin

NMPA:

National Medical Products Administration

DCR:

Disease control rate

TV:

Tisotumab vedotin

TF:

Tissue factor

NSCLC:

Non-small cell lung cancer

r/mCC:

Recurrent or metastatic cervical cancer

LT:

Loncastuximab tesirine

PBD:

Pyrrolobenzodiazepine

MIRV:

Mirvetuximab soravtansin

FRα:

Folate receptor α

PE38:

Pseudomonas exotoxin A

DM4:

Maytansinoid

DXd:

Deruxtecan

DAR:

Drug-to-antibody ratio

PARP:

Poly-ADP ribose polymerase

AR:

Androgen receptor

Wnt:

Wingless-related integration site

PI3K:

Phosphoinositide 3-kinase

mTOR:

Mechanistic target of rapamycin

TGF-β:

Transforming growth factor beta

OS:

Overall survival

PFS:

Progression-free survival

IM:

Immunomodulatory

LAR:

Luminal androgen receptor

BL-1:

Basal-like 1

BL-2:

Basal-like 2

M:

Mesenchymal

MSL:

Mesenchymal stem-like

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  1. Department of Pharmaceutical Chemistry, Yashwantrao Bhonsale College of Pharmacy, Affiliated to Mumbai University, Sawantwadi, 416510, India

    Sanjana Sawant, Gaurav Gopal Naik & Vijay A. Jagtap

  2. IIT BHU, Varanasi, 221005, India

    Alakh N. Sahu

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SNS: writing review and editing, conceptualization. GGN: writing original draft and review. ANS & VAJ: conceptualization.

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Sawant, S., Naik, G.G., Sahu, A.N. et al. Understanding the chemistry & pharmacology of antibody–drug conjugates in triple-negative breast cancer with special reference to exatecan derivatives. Med Oncol 41, 301 (2024). https://doi.org/10.1007/s12032-024-02542-y

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