A Patent Review on FDA‐Approved Antibody‐Drug Conjugates, Their Linkers and Drug Payloads

Chia, C. S. Brian

doi:10.1002/cmdc.202200032

Cited by 40 publications

(30 citation statements)

References 82 publications

(138 reference statements)

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“…This theoretically leads to less toxicity with directed drug delivery sparing normal tissues, and enhancing cancer response. 19 Enfortumab vedotin is an ADC comprised of an human monoclonal antibody to nectin-4, linked to cytotoxic payload monomethyl auristatin E (MMAE), which is a microtubule-disrupting compound. 20 Nectin-4 is primarily expressed in embryo, placenta, and skin, and is overexpressed by a number of cancers, including urothelial and breast cancers.…”

Section: Introductionmentioning

confidence: 99%

Targeted Treatment of Locally Advanced and Metastatic Urothelial Cancer: Enfortumab Vedotin in Context

Hoffman-Censits¹,

Maldonado²

2022

OTT

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Enfortumab vedotin (EV) is a novel antibody-drug conjugate that is the first in class to be FDA-approved for use in patients with treatment-refractory urothelial cancer. Enfortumab is comprised of an antibody targeting nectin-4, widely expressed in urothelial cancers, with an monomethyl auristatin E (MMAE) chemotherapy payload. To date, trials in urothelial cancers refractory to platinumbased chemotherapy, and or checkpoint inhibitors, have shown the drug is very active, with overall responses ranging from 40% to 52%. This includes patients with visceral metastasis, a known predictor of poor prognosis. EV is fairly well tolerated, including in patients who are not candidates for cisplatin, a common urothelial cancer population with significant unmet need. Side effects such as skin toxicity, fatigue, and blood sugar elevations are generally manageable with supportive care and dose modifications. Peripheral neuropathy is common and can be dose-limiting in responding patients, and rare serious skin toxicities have been reported. Trials in various disease states and in combination with checkpoint inhibitors and other agents are ongoing, with additional indications likely in the future for EV in urothelial cancer.

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Section: Introductionmentioning

confidence: 99%

Targeted Treatment of Locally Advanced and Metastatic Urothelial Cancer: Enfortumab Vedotin in Context

Hoffman-Censits¹,

Maldonado²

2022

OTT

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“…Given the biological relevance and structural complexity of these classes of cancer therapeutics, many reviews have been devoted to all aspects of the ADCs, including general details [ 20 , 21 , 24 , 25 , 26 , 28 , 29 , 34 , 35 , 36 , 37 , 38 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ], the role of the linker [ 30 , 32 , 33 ] as well as the clinical status of ADCs [ 56 , 57 , 58 , 59 ]. As described in the Introduction, ADCs rely on several fields: the antibody belongs to biology and biochemistry, while the linker and payload fall into organic chemistry.…”

Section: Introductionmentioning

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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“…Owing to the highly selective behavior of ADCs in delivering potent cytotoxic drugs to tumor cells in xenograft models, they are developed as a part of targeted therapies to expand the therapeutic window and reduce the adverse effects 2,3 . Recently, more than ten cancer therapeutic drugs, such as gemtuzumab ozogamicin (Mylotarg®) and brentuximab vedotin (Adcetris®), were approved by the US Food and Drug Administration and many ADC candidates still are subjected to clinical studies, which suggests the success of the ADC strategy for cancer therapy 4,5 …”

Section: Introductionmentioning

confidence: 99%

“…2,3 Recently, more than ten cancer therapeutic drugs, such as gemtuzumab ozogamicin (Mylotarg®) and brentuximab vedotin (Adcetris®), were approved by the US Food and Drug Administration and many ADC candidates still are subjected to clinical studies, which suggests the success of the ADC strategy for cancer therapy. 4,5 Concurrently with the development of antibody drugs, some studies report the design and development of a wide variety of antibody mimetics. [6][7][8] Recent advances in the protein computational design enabled the systematic development of antibody-mimetic, 9,10 which has great potential for new therapeutic agents like ADCs.…”

Section: Introductionmentioning

confidence: 99%

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Pathological complete remission of relapsed tumor by photo‐activating antibody–mimetic drug conjugate treatment

et al. 2022

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Antibody–mimetic drug conjugate is a novel noncovalent conjugate consisting of an antibody‐mimetic recognizing a target molecule on the cancer cell surface and low‐molecular‐weight payloads that kill the cancer cells. In this study, the efficacy of a photo‐activating antibody–mimetic drug conjugate targeting HER2‐expressing tumors was evaluated in mice, by using the affibody that recognize HER2 (ZHER2:342) as a target molecule and an axially substituted silicon phthalocyanine (a novel potent photo‐activating compound) as a payload. The first treatment with the photo‐activating antibody–mimetic drug conjugates reduced the size of all HER2‐expressing KPL‐4 xenograft tumors macroscopically. However, during the observation period, relapsed tumors gradually appeared in approximately 50% of the animals. To evaluate the efficacy of repeated antibody–mimetic drug conjugate treatment, animals with relapsed tumors were treated again with the same regimen. After the second observation period, the mouse tissues were examined histopathologically. Unexpectedly, all relapsed tumors were eradicated, and all animals were diagnosed with pathological complete remission. After the second treatment, skin wounds healed rapidly, and no significant side effects were observed in other organs, except for occasional microscopic granulomatous tissues beneath the serosa of the liver in a few mice. Repeated treatments seemed to be well tolerated. These results indicate the promising efficacy of the repeated photo‐activating antibody–mimetic drug conjugate treatment against HER2‐expressing tumors.

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A Patent Review on FDA‐Approved Antibody‐Drug Conjugates, Their Linkers and Drug Payloads

Cited by 40 publications

References 82 publications

Targeted Treatment of Locally Advanced and Metastatic Urothelial Cancer: Enfortumab Vedotin in Context

Targeted Treatment of Locally Advanced and Metastatic Urothelial Cancer: Enfortumab Vedotin in Context

Antibody-Drug Conjugates Containing Payloads from Marine Origin

Pathological complete remission of relapsed tumor by photo‐activating antibody–mimetic drug conjugate treatment

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