Therapeutic Potential of MF-TTZ-MMAE, a Site-Specifically Conjugated Antibody-Drug Conjugate, for the Treatment of HER2-Overexpressing Breast Cancer

Juen, Ludovic; Baltus, Christine B.; Gély, Camille; Kervarrec, Thibault; Feuillâtre, Ofelia; Desgranges, Audrey; Viaud‐Massuard, Marie‐Claude; Martin, Camille

doi:10.1021/acs.bioconjchem.2c00015

Cited by 3 publications

(3 citation statements)

References 34 publications

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“…Enzymatic methods offer another layer of specificity by using enzymes that recognize specific peptide or carbohydrate motifs on antibodies for payload attachment. Among the most exciting advancements are Tag-free enzymatic methods that negate the need for engineered tags on antibodies, simplifying the process and potentially improving the manufacturability and scalability of ADC production [78][79][80]. These methods utilize naturally occurring glycan sites on antibodies for the attachment of payloads using glycan-specific enzymes, allowing for a homogeneous product without the need for genetic modification of the antibody.…”

Section: Future Directionsmentioning

confidence: 99%

Next-Generation HER2-Targeted Antibody–Drug Conjugates in Breast Cancer

Zimmerman,

Esteva

2024

Cancers

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Human epidermal growth factor receptor 2 (HER2) tyrosine kinase is overexpressed in 20% of breast cancers and associated with a less favorable prognosis compared to HER2-negative disease. Patients have traditionally been treated with a combination of chemotherapy and HER2-targeted monoclonal antibodies such as trastuzumab and pertuzumab. The HER2-targeted antibody–drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) represent a novel class of therapeutics in breast cancer. These drugs augment monoclonal antibodies with a cytotoxic payload, which is attached by a linker, forming the basic structure of an ADC. Novel combinations and sequential approaches are under investigation to overcome resistance to T-DM1 and T-DXd. Furthermore, the landscape of HER2-targeted therapy is rapidly advancing with the development of ADCs designed to attack cancer cells with greater precision and reduced toxicity. This review provides an updated summary of the current state of HER2-targeted ADCs as well as a detailed review of investigational agents on the horizon. Clinical trials are crucial in determining the optimal dosing regimens, understanding resistance mechanisms, and identifying patient populations that would derive the most benefit from these treatments. These novel ADCs are at the forefront of a new era in targeted cancer therapy, holding the potential to improve outcomes for patients with HER2-positive and HER2-Low breast cancer.

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Section: Future Directionsmentioning

confidence: 99%

Next-Generation HER2-Targeted Antibody–Drug Conjugates in Breast Cancer

Zimmerman,

Esteva

2024

Cancers

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“…Juen et al used a novel technology: HER2-targeting ADC, antibody-drug conjugates with monomethyl auristatin improved antibody-drug (trastuzumab) transport, and internalization of the cytotoxic agent. It also observed a positive effect on HER2 xenograft tumor models in mice [ 89 ]. Chemotherapy still remains the first line of defence for triple-negative breast/TNBC tumors even in combination with endocrine therapies.…”

Section: Treatment Of Solid Tumors With Ectmentioning

confidence: 99%

Electrochemotherapy: An Alternative Strategy for Improving Therapy in Drug-Resistant SOLID Tumors

Condello

D'Avack

Spugnini³

et al. 2022

Cancers

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Electrochemotherapy (ECT) is one of the innovative strategies to overcome the multi drug resistance (MDR) that often occurs in cancer. Resistance to anticancer drugs results from a variety of factors, such as genetic or epigenetic changes, an up-regulated outflow of drugs, and various cellular and molecular mechanisms. This technology combines the administration of chemotherapy with the application of electrical pulses, with waveforms capable of increasing drug uptake in a non-toxic and well tolerated mechanical system. ECT is used as a first-line adjuvant therapy in veterinary oncology, where it improves the efficacy of many chemotherapeutic agents by increasing their uptake into cancer cells. The chemotherapeutic agents that have been enhanced by this technique are bleomycin, cisplatin, mitomycin C, and 5-fluorouracil. After their use, a better localized control of the neoplasm has been observed. In humans, the use of ECT was initially limited to local palliative therapy for cutaneous metastases of melanoma, but phase I/II studies are currently ongoing for several histotypes of cancer, with promising results. In this review, we described the preclinical and clinical use of ECT on drug-resistant solid tumors, such as head and neck squamous cell carcinoma, breast cancer, gynecological cancer and, finally, colorectal cancer.

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“…Accordingly, the authors initially prepared the ADC with the antibody brentuximab and compared it with the brentuximab vedotin (Adcetris) as proof of the concept of this new strategy. Then, after ligation of the linker-drug derivative 54 , based on the monomethyl auristatin E ( 3 ) , with the reduced anti-CD30 chimeric immunoglobulin G subclass cAC10 mAb, furnished ADC 55 , whose characterization led to a stable and homogeneous DAR distribution of 4, and excellent stability in the presence of thiol-containing proteins, such as human serum albumin (HSA), and a similar efficacy profile to Adcetris in a Karpas 299 xenograft model of CD30-positive lymphoma, with complete tumor regression in all mice when treated once at 1 mg/kg of 55 [ 112 ] . Encouraged by these results, the authors extended their technology to other antibodies such as trastuzumab (ADC 56 ) and a CD56-targeting antibody (ADC 57 ), which was called Adcitmer [ 113 ].…”

Section: Chemistry and Biology Of Marine Antibody-drug Conjugatesmentioning

confidence: 99%

Antibody-Drug Conjugates Containing Payloads from Marine Origin

et al. 2022

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Antibody-drug conjugates (ADCs) are an important class of therapeutics for the treatment of cancer. Structurally, an ADC comprises an antibody, which serves as the delivery system, a payload drug that is a potent cytotoxin that kills cancer cells, and a chemical linker that connects the payload with the antibody. Unlike conventional chemotherapy methods, an ADC couples the selective targeting and pharmacokinetic characteristics related to the antibody with the potent cytotoxicity of the payload. This results in high specificity and potency by reducing off-target toxicities in patients by limiting the exposure of healthy tissues to the cytotoxic drug. As a consequence of these outstanding features, significant research efforts have been devoted to the design, synthesis, and development of ADCs, and several ADCs have been approved for clinical use. The ADC field not only relies upon biology and biochemistry (antibody) but also upon organic chemistry (linker and payload). In the latter, total synthesis of natural and designed cytotoxic compounds, together with the development of novel synthetic strategies, have been key aspects of the consecution of clinical ADCs. In the case of payloads from marine origin, impressive structural architectures and biological properties are observed, thus making them prime targets for chemical synthesis and the development of ADCs. In this review, we explore the molecular and biological diversity of ADCs, with particular emphasis on those containing marine cytotoxic drugs as the payload.

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Therapeutic Potential of MF-TTZ-MMAE, a Site-Specifically Conjugated Antibody-Drug Conjugate, for the Treatment of HER2-Overexpressing Breast Cancer

Cited by 3 publications

References 34 publications

Next-Generation HER2-Targeted Antibody–Drug Conjugates in Breast Cancer

Next-Generation HER2-Targeted Antibody–Drug Conjugates in Breast Cancer

Electrochemotherapy: An Alternative Strategy for Improving Therapy in Drug-Resistant SOLID Tumors

Antibody-Drug Conjugates Containing Payloads from Marine Origin

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