Discoidin domain receptor 1(DDR1)is overexpressed in various tumors,such as triple-negative breast cancer(TNBC),and is rarely expressed in normal tissues.These characteristics make DDR1 a preferable target candidate f...Discoidin domain receptor 1(DDR1)is overexpressed in various tumors,such as triple-negative breast cancer(TNBC),and is rarely expressed in normal tissues.These characteristics make DDR1 a preferable target candidate for the construction of an antibody-drug conjugate(ADC)for targeted therapy.Here,we investigated the preparation and preclinical efficacy of DDR1-DX8951,an ADC that includes an anti-DDR1 monoclonal antibody conjugated to DX8951 by a cleavable Gly-Gly-Phe-Gly(GGFG)linker.The anti-DDR1 monoclonal antibody was coupled to DX8951(i.e.,DDR1-DX8951),producing the targeted therapy ADC.The antitumor activities of DDR1-DX8951 monotherapy or DDR1-DX8951 plus pembrolizumab were assessed in TNBC mouse models.DDR1-DX8951 can specifically target DDR1,be quickly internalized by TNBC cells,and reduce the viability of TNBC cells in vitro.The potent antitumor activity of DDR1-DX8951 was revealed in TNBC xenograft models.Importantly,our investigation demonstrated that DDR1-DX8951 plus pembrolizumab not only revealed the inhibitory efficacy on tumor growth and metastasis but also played an important role in improving the immunosuppressive tumor microenvironment(TME)of TNBC.Taken together,this investigation provides justification for large-sample studies to further assess the safety and efficacy of DDR1-DX8951 plus pembrolizumab for TNBC clinical trials.展开更多
Given the critical shortage of antibody-drug conjugates(ADCs)for bladder cancer(BCa),we developed a novel FGFR3-targeted ADC,LZU-WZLYFG001,composed of a humanized anti-FGFR3 IgG1 monoclonal antibody,a cleavable GGFG l...Given the critical shortage of antibody-drug conjugates(ADCs)for bladder cancer(BCa),we developed a novel FGFR3-targeted ADC,LZU-WZLYFG001,composed of a humanized anti-FGFR3 IgG1 monoclonal antibody,a cleavable GGFG linker,and the payload DXD.The antibody was engineered in 293 cells and conjugated via thiol-based chemistry,achieving a drug-to-antibody ratio(DAR)of eight.Comprehensive preclinical assessments,including in vitro and in vivo studies using BCa cells,organoids,cell-derived xenograft and patient-derived xenograft(PDX)models,were conducted to evaluate efficacy,targeting ability,mechanism,safety and tissue distribution.LZU-WZLYFG001 demonstrated high purity,targeting specificity and low endotoxin levels,and it significantly inhibited BCa cell proliferation,migration and invasion at nanomolar concentrations,with efficacy strongly associated with FGFR3 expression levels.Mechanistic studies showed binding to FGFR3,internalization and lysosomal release of LZU-WZLYFG001.In organoid and xenograft models,LZU-WZLYFG001 exhibited superior efficacy compared with the gemcitabine+cisplatin(GC)regimen,particularly in GC-resistant PDX tumors,while also showing robust 3D penetration,a bystander effect,and no significant short-term toxicity.展开更多
Metastatic urothelial carcinoma(mUC)is a challenging malignancy with historically limited treatment options.Advances in understanding its biology have enabled the development of innovative therapies,including immune c...Metastatic urothelial carcinoma(mUC)is a challenging malignancy with historically limited treatment options.Advances in understanding its biology have enabled the development of innovative therapies,including immune checkpoint inhibitors and antibody-drug conjugates(ADCs).ADCs,such as enfortumab vedotin,sacituzumab govitecan,and trastuzumab deruxtecan,represent transformative advancements,offering targeted delivery of cytotoxic agents.This review highlights the evolving role of ADCs in mUC,examining their mechanisms,clinical efficacy,patient selection criteria,genetic insights,and future directions in personalized treatment strategies.展开更多
Limited clinical application of antibody-drug conjugates(ADCs)targeting tumor associated antigens(TAAs)is usually caused by on-target off-tumor side effect.Tumor-specific mutant antigens(TSMAs)only expressed in tumor ...Limited clinical application of antibody-drug conjugates(ADCs)targeting tumor associated antigens(TAAs)is usually caused by on-target off-tumor side effect.Tumor-specific mutant antigens(TSMAs)only expressed in tumor cells which are ideal targets for ADCs.In addition,intracellular somatic mutant proteins can be presented on the cell surface by human leukocyte antigen class I(HLA I)molecules forming tumor-specific peptide/HLA I complexes.KRAS G12 V mutation frequently occurred in varied cancer and was verified as a promising target for cancer therapy.In this study,we generated two TCR-mimic antibodydrug conjugates(TCRm-ADCs),2E8-MMAE and 2 A5-MMAE,targeting KRAS G12 V/HLAA*0201 complex,which mediated specific antitumor activity in vitro and in vivo without obvious toxicity.Our findings are the first time validate the strategy of TCRm-ADCs targeting intracellular TSMAs,which improves the safety of antibody-based drugs and provides novel strategy for precision medicine in cancer therapy.展开更多
The past few years have witnessed enormous progresses in the development of antibody-drug conjugates(ADCs).Consequently,comprehensive analysis of ADCs in biological systems is critical in supporting discovery,developm...The past few years have witnessed enormous progresses in the development of antibody-drug conjugates(ADCs).Consequently,comprehensive analysis of ADCs in biological systems is critical in supporting discovery,development and evaluation of these agents.Liquid chromatography-mass spectrometry(LC-MS)has eme rged as a promising and versatile tool for ADC analysis across a wide range of scenarios,owing to its multiplexing ability,rapid method development,as well as the capability of analyzing a variety of targets ranging from small-molecule payloads to the intact protein with a high,molecular resolution.However,despite this tremendous potential,challenges persist due to the high complexity in both the ADC molecules and the related biological systems.This review summarizes the up-to-date LC-MS-based strategies in ADC analysis and discusses the challenges and opportunities in this rapidly-evolving field.展开更多
Self-immolative linkers have been widely used to construct prodrugs to improve their efficacy and safety.In this study,we report the use of phenoxysilyl linker as a self-immolative unit to prepare antibody-drug conjug...Self-immolative linkers have been widely used to construct prodrugs to improve their efficacy and safety.In this study,we report the use of phenoxysilyl linker as a self-immolative unit to prepare antibody-drug conjugates(ADCs).Phenoxysily based ADC Ate-PPS-CA4 was prepared and its release was systematically investigated by mass spectrometry.Biological evaluation showed that Ate-PPS-CA4 displayed the ability to target delivery and self-immolative release the active payload CA4 on PD-L1 positive cells MDA-MB-231.As the same with its payload CA4,it could arrest the cell cycle to the G2/M phase and induced changes in cell morphology at the dose of its IC_(50).The development of this linker with novel drug release mechanisms will expand the methodology to construct ADCs,especially for non-internalizing ADCs by extracellular cleavage.展开更多
Over the past several decades, there has been a significant surge in the development of Antibody-Drug Conjugates (ADCs). Designing an ideal ADC presents a multifaceted challenge, requiring the precise orchestration of...Over the past several decades, there has been a significant surge in the development of Antibody-Drug Conjugates (ADCs). Designing an ideal ADC presents a multifaceted challenge, requiring the precise orchestration of various elements such as antigens, antibodies, linkers, and payloads. While ADCs aim to target tumor cells specifically, several antigens can also be found in regular tissues, potentially compromising the specificity of ADCs in therapeutic applications. The complexity extends to antibody selection, necessitating effective targeting of the desired antigen and ensuring compatibility with linkers for effective payload delivery. Additionally, the linker and payload combination are critical for the ADC’s therapeutic efficiency, balancing stability in circulation and timely payload release upon target binding. ADC doses must be safe for normal tissues while ensuring the released payloads are effective. The success of ADCs is attributed to their unmatched efficacy compared to traditional chemotherapy agents. The current research article aims to provide a technical review of Antibody-Drug Conjugates (ADCs) for cancer therapies. A brief discussion on the basics of ADCs, regulatory approach, overview, and technical complexities for quantification is presented. This review also summarizes recently approved ADCs and introduces the concepts of antibodies, linkers, and payloads. The article also outlines cancer-specific ADCs currently in late-stage clinical trials for cancer treatment.展开更多
Gynecological cancer poses a serious threat to women's health.Despite significant advances in immunotherapy and targeted therapeutic strategies for gynecological cancers,substantial challenges persist,including li...Gynecological cancer poses a serious threat to women's health.Despite significant advances in immunotherapy and targeted therapeutic strategies for gynecological cancers,substantial challenges persist,including limited response rates,inevitable resistance,and adverse effects.In recent years,a milestone in gynecological cancer therapy has been the approval of antibody-drug conjugates(ADCs).In this review,we provide a comprehensive overview of the structural features,mechanisms of action,and molecular characteristics of ADCs that have been approved and are currently under development.Their clinical applications and associated challenges have also been highlighted.Finally,we discuss the prospects of ADCs in the treatment of gynecological cancers.展开更多
Pancreatic cancer,mainly pancreatic ductal adenocarcinoma(PDAC),is aggressive with poor prognosis.Because its clinical manifestations appear at advanced stages,only less than 20%of patients with PDAC can undergo radic...Pancreatic cancer,mainly pancreatic ductal adenocarcinoma(PDAC),is aggressive with poor prognosis.Because its clinical manifestations appear at advanced stages,only less than 20%of patients with PDAC can undergo radical surgery.Chemotherapy,with strong toxic side effects,remains the main therapy.Therefore,developing more effective strategies for PDAC is warranted.Because of its heterogeneity and highly immunosuppressive tumor microenvironment(TME),the discovery of new drug targets and development of new therapeutic modalities for PDAC remain difficult.Antibody-drug conjugates(ADCs)—which have demonstrated efficacy against various types of cancers—improve the antitumor effects of a drug by enhancing tumor targeting,reducing toxic side effects,and increasing TME interactions via antigen presentation regulation and immunosuppressive cell inhibition.Here,we summarized the effects of ADCs on TME of PDAC,as well as the future research prospects.展开更多
Antibody-drug conjugates(ADCs)represent a promising approach in targeted cancer therapy,combining the tar-geted precision of antibodies with the potency of cytotoxic payloads to selectively target tumour cell whilst m...Antibody-drug conjugates(ADCs)represent a promising approach in targeted cancer therapy,combining the tar-geted precision of antibodies with the potency of cytotoxic payloads to selectively target tumour cell whilst min-imising off-target effects.This review provides a comprehensive analysis of ADCs,encompassing their structural components,mechanisms of action,and clinical applications.It also examines recent technological advancements,particularly in antibody engineering and linker design,aimed at enhancing therapeutic efficacy and safety.The current clinical landscape is outlined,highlighting approved ADCs and promising candidates in clinical trials,while also addressing key challenges such as stability,half-life,and systemic toxicity.This review is based on an extensive literature survey from major databases such as Scopus and Web of Science,with a focus on keywords like“antibody-drug conjugates”,“ADC advancements”,and“next-generation ADC technologies”.By integrating insights from both preclinical and clinical perspectives,we highlight the transformative potential of ADCs in advancing modern cancer therapy.展开更多
Antibody-drug conjugates(ADCs)represent a promising class of targeted cancer therapeutics that combine the specificity of monoclonal antibodies with the potency of cytotoxic payloads.Despite their therapeutic potentia...Antibody-drug conjugates(ADCs)represent a promising class of targeted cancer therapeutics that combine the specificity of monoclonal antibodies with the potency of cytotoxic payloads.Despite their therapeutic potential,the use of ADCs faces significant challenges,including off/on-target toxicity and resistance development.This review examines the current landscape of ADC development,focusing on the critical aspects of target selection and antibody engineering.We discuss strategies to increase ADC efficacy and safety,including multitarget approaches,pH-dependent antibodies,and masked peptide technologies.The importance of comprehensive antigen expression profiling in both tumor and normal tissues is emphasized,highlighting the role of advanced technologies,such as single-cell sequencing and artificial intelligence,in optimizing target selection.Furthermore,we explore combina-tion therapies and innovations in linker-payload chemistry,which may provide approaches for expanding the ther-apeutic window of ADCs.These advances pave the way for the development of more precise and effective cancer treatments,potentially extending ADC applications beyond oncology.展开更多
Cancer is the second leading cause of death globally.Its treatment remains a major challenge due to the disease's complexity,heterogeneity,and adaptive nature.Among the array of available treatments,targeted thera...Cancer is the second leading cause of death globally.Its treatment remains a major challenge due to the disease's complexity,heterogeneity,and adaptive nature.Among the array of available treatments,targeted therapy emerges as a paramount approach to address this substantial unmet clinical need,owing to its precise tumor targeting capabilities and potential for mitigating tumor progression risks.Drug conjugates are in high demand for targeted therapy due to their unique ligand specificity and potent cytotoxicity,thereby significantly enhancing therapeutic efficacy and reducing the incidence of adverse effects.Therefore,as a burgeoning field in biomedical research,it is timely to outline the latest advances in drug conjugates-driven cancer treatment.Herein,we aim to present the emerging breakthroughs in this exciting field at the intersection of target ligands,linkers,payloads,and cancer treatments.This review focuses on several drug conjugates-related strategies,including antibody-drug conjugates(ADCs),peptide-drug conjugates(PDCs),small molecule-drug conjugates(SMDCs),aptamer-drug conjugates(ApDCs)and radionuclide-drug conjugates(RDCs).Finally,we discuss the fundamentals behind drug conjugate-based anticancer therapeutics,along with their inherent advantages and associated challenges,as well as recent research advances.展开更多
The antibody-drug conjugate （ADC）, a humanized or human monoclonal antibody conjugated with highly cytotoxic small molecules （payloads） through chemical linkers, is a novel therapeutic format and has great potenti...The antibody-drug conjugate （ADC）, a humanized or human monoclonal antibody conjugated with highly cytotoxic small molecules （payloads） through chemical linkers, is a novel therapeutic format and has great potential to make a paradigm shift in cancer chemother- apy. This new antibody-based molecular platform enables selective delivery of a potent cytotoxic payload to target cancer cells, resulting in improved efficacy, reduced systemic toxicity, and preferable pharmacokinetics （PK）I pharmacodynamics （PD） and biodistribution compared to traditional chemotherapy. Boosted by the successes of FDA-approved Adcetris~ and Kadcyla~, this drug class has been rapidly growing along with about 60 ADCs cur- rently in clinical trials. In this article, we briefly review molecular aspects of each component （the antibody, payload, and linker） of ADCs, and then mainly discuss traditional and new technologies of the conjugation and linker chemistries for successful construction of clini- cally effective ADCs. Current efforts in the conjugation and linker chemistries will provide greater insights into molecular design and strategies for clinically effective ADCs from medicinal chemistry and pharmacology standpoints. The development of site-specific conjuga- tion methodologies for constructing homogeneous ADCs is an especially promising path to improving ADC design, which will open the way for novel cancer therapeutics.展开更多
Antibody-drug conjugates(ADCs)are gradually revolutionizing clinical cancer therapy.The antibody-drug conjugate linker molecule determines both the efficacy and the adverse effects,and so has a major influence on the ...Antibody-drug conjugates(ADCs)are gradually revolutionizing clinical cancer therapy.The antibody-drug conjugate linker molecule determines both the efficacy and the adverse effects,and so has a major influence on the fate of ADCs.An ideal linker should be stable in the circulatory system and release the cytotoxic payload specifically in the tumor.However,existing linkers often release payloads nonspecifically and inevitably lead to off-target toxicity.This defect is becoming an increasingly important factor that restricts the development of ADCs.The pursuit of ADCs with optimal therapeutic windows has resulted in remarkable progress in the discovery and development of novel linkers.The present review summarizes the advance of the chemical trigger,linker-antibody attachment and linker-payload attachment over the last 5 years,and describes the ADMET properties of ADCs.This work also helps clarify future developmental directions for the linkers.展开更多
Antibody-drug conjugates(ADCs)are a rapidly developing therapeutic approach in cancer treatment that has shown remarkable activity in breast cancer.Currently,there are two ADCs approved for the treatment of human epid...Antibody-drug conjugates(ADCs)are a rapidly developing therapeutic approach in cancer treatment that has shown remarkable activity in breast cancer.Currently,there are two ADCs approved for the treatment of human epidermal growth factor receptor 2-positive breast cancer,one for triple-negative breast cancer,and multiple investigational ADCs in clinical trials.However,drug resistance has been noticed in clinical use,especially in trastuzumab emtansine.Here,the mechanisms of ADC resistance are summarized into four categories:antibodymediated resistance,impaired drug trafficking,disrupted lysosomal function,and payload-related resistance.To overcome or prevent resistance to ADCs,innovative development strategies and combination therapy options are being investigated.Analyzing predictive biomarkers for optimal therapy selection may also help to prevent drug resistance.展开更多
Background:Disitamab vedotin(DV;RC48-ADC)is an antibody-drug conjugate comprising a human epidermal growth factor receptor 2(HER2)-directed antibody,linker and monomethyl auristatin E.Preclinical studies have shown th...Background:Disitamab vedotin(DV;RC48-ADC)is an antibody-drug conjugate comprising a human epidermal growth factor receptor 2(HER2)-directed antibody,linker and monomethyl auristatin E.Preclinical studies have shown that DV demonstrated potent antitumor activity in preclinical models of breast,gastric,and ovarian cancers with different levels of HER2 expression.In this pooled analysis,we report the safety and efficacy of DV in patients with HER2-overexpression and HER2-low advanced breast cancer(ABC).Methods:In the phase I dose-escalation study(C001 CANCER),HER2-overexpression ABC patients received DV at doses of 0.5-2.5 mg/kg once every two weeks(Q2W)until unacceptable toxicity or progressive disease.The dose range,safety,and pharmacokinetics(PK)were determined.The phase Ib dose-range and expansion study(C003 CANCER)enrolled two cohorts:HER2-overexpression ABC patients receiving DV at doses of 1.5-2.5 mg/kg Q2W,with the recommended phase 2 dose(RP2D)determined,andHER2-lowABC patients receiving DV at doses of 2.0 mg/kg Q2W to explore the efficacy and safety of DV in HER2-low ABC.Results:Twenty-four patients with HER2-overexpression ABC in C001 CANCER,46 patients with HER2-overexpressionABCand 66 patients with HER2-low ABC in C003 CANCER were enrolled.At 2.0 mg/kg RP2D Q2W,the confirmed objective response rates were 42.9%(9/21;95%confidence interval[CI]:21.8%-66.0%)and 33.3%(22/66;95%CI:22.2%-46.0%),with median progression-free survival(PFS)of 5.7 months(95%CI:5.3-8.4 months)and 5.1 months(95%CI:4.1-6.6 months)for HER2-overexpression and HER2-low ABC,respectively.Common(≥5%)grade 3 or higher treatment-emergent adverse events included neutrophil count decreased(17.6%),gamma-glutamyl transferase increased(13.2%),asthenia(11.0%),white blood cell count decreased(9.6%),peripheral neuropathy such as hypoesthesia(5.9%)and neurotoxicity(0.7%),and pain(5.9%).Conclusion:DV demonstrated promising efficacy in HER2-overexpression and HER2-low ABC,with a favorable safety profile at 2.0 mg/kg Q2W.展开更多
Antibody-drug conjugates(ADCs)combine the high specificity of monoclonal antibodies with the high anti-tumor activity of small molecular cytotoxic payloads.The anti-tumor activity of ADCs is mainly achieved by the dir...Antibody-drug conjugates(ADCs)combine the high specificity of monoclonal antibodies with the high anti-tumor activity of small molecular cytotoxic payloads.The anti-tumor activity of ADCs is mainly achieved by the direct blocking of the receptor by monoclonal antibodies,direct action and bystander effect of cytotoxic drugs,and antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity.ADCs have been used in adjuvant therapy and rescue treatment of human epidermal receptor 2(HER2)-positive breast cancer,greatly improving the prognosis of breast cancer patients.Several ongoing clinical trials of ADC for breast cancer and other solid tumors proved the potential of ADCs will provide more promising treatment options for patients with malignant tumors.This review introduces the mechanism and latest clinical progress of ADC drugs approved for HER2-positive breast cancer to guide clinical practice and conduct research.展开更多
The ability to chemically modify monoclonal antibodies with the attachment of specific functional groups has opened up an enormous range of possibilities for the targeted treatment and diagnosis of cancer in the clini...The ability to chemically modify monoclonal antibodies with the attachment of specific functional groups has opened up an enormous range of possibilities for the targeted treatment and diagnosis of cancer in the clinic.As the number of such antibody-based drug candidates has increased,so too has the need for more stringent and robust preclinical evaluation of their in vivo performance to maximize the likelihood that time,research effort,and money are only spent developing the most effective and promising candidate molecules for translation to the clinic.Concurrent with the development of antibody-drug conjugate(ADC)technology,several recent advances in preclinical research stand to greatly increase the experimental rigor by which promising candidate molecules can be evaluated.These include advances in preclinical tumor modeling with the development of patient-derived tumor organoid models that far better recapitulate many aspects of the human disease than conventional subcutaneous xenograft models.Such models are amenable to genetic manipulation,which will greatly improve our understanding of the relationship between ADC and antigen and stringently evaluate mechanisms of therapeutic response.Finally,tumor development is often not visible in these in vivo models.We discuss how the application of several preclinical molecular imaging techniques will greatly enhance the quality of experimental data,enabling quantitative pre-and post-treatment tumor measurements or the precise assessment of ADCs as effective diagnostics.In our opinion,when taken together,these advances in preclinical cancer research will greatly improve the identification of effective candidate ADC molecules with the best chance of clinical translation and cancer patient benefit.展开更多
Human epidermal growth factor 2(HER2)-positive breast cancer(BC)represents nearly 20%of all breast tumors.Historically,these patients had ahigh rate of relapse and dismal prognosis.The advent of HER2-targeting monoclo...Human epidermal growth factor 2(HER2)-positive breast cancer(BC)represents nearly 20%of all breast tumors.Historically,these patients had ahigh rate of relapse and dismal prognosis.The advent of HER2-targeting monoclonal antibodies such astrastuzumab followed by pertuzumab had improved the prognosis of HER2-positive metastatic BC.More recently,antibody-drug conjugates(ADCs)are now reshaping the treatment paradigm of solid tumors,especially breastcancer.Tratsuzumab emtansine(T-DM1)was one of the first ADC developed in oncology and was approved forthe management of HER2-positive metastatic BC.In a head-to-head comparison,trastuzumab deruxtecan(T-DXd)defeated T-DM1 as a second-line treatment.The efficacy of ADCs is counterbalanced by the appearance ofacquired resistance to these agents.In this paper,we summarize the mechanisms of action and resistance ofT-DM1 and T-DXd,as well as their clinical efficacy.Additionally,we also discuss potential strategies for addressingresistance to ADC.展开更多
Monoclonal antibody-drug conjugate was applied in a clinical trial for patients with bladder cancer, Monoclonal antibody HB7A from a mouse splenocyte immunized against human bladder cancer was used as a drug carrier, ...Monoclonal antibody-drug conjugate was applied in a clinical trial for patients with bladder cancer, Monoclonal antibody HB7A from a mouse splenocyte immunized against human bladder cancer was used as a drug carrier, The anti-cancer drug adriamycin (ADR) was bound to HB7A through a dextran (DEX) bridge to form the conjugate HB7A-DEX-ADR. The in vitro cytotoxic effect of the conjugate on BIU-87 bladder cancer cells was similar to that of free ADR and the mixture of HB7A and ADR, Seven patients with bladder cancer were given HB7A-DEX-ADR intravenously. The immunoperoxidast studies of the resected specimens showed that HB7A was localized specifically in cancer, and histological studies revealed degenerative and necrotic changes of the tumor cells, Patients receiving the conjugate did not experience serious side effects, This study suggests that immunotargeting chemotherapy with HB7A-DEX-ADR is well tolerated by patients and its cytotoxicity on tumor is substantial.展开更多
基金supported by Anhui Province Clinical Key Specialty Construction Project,China(Grant No.:2021sjlczdzk)the National Key Research and Development Program of China(Grants Nos.:2022YFC2304102 and 2022YFC2303300)the National Natural Science Foundation of China(Grant Nos.:82272301,32100745,and 31971129).
文摘Discoidin domain receptor 1(DDR1)is overexpressed in various tumors,such as triple-negative breast cancer(TNBC),and is rarely expressed in normal tissues.These characteristics make DDR1 a preferable target candidate for the construction of an antibody-drug conjugate(ADC)for targeted therapy.Here,we investigated the preparation and preclinical efficacy of DDR1-DX8951,an ADC that includes an anti-DDR1 monoclonal antibody conjugated to DX8951 by a cleavable Gly-Gly-Phe-Gly(GGFG)linker.The anti-DDR1 monoclonal antibody was coupled to DX8951(i.e.,DDR1-DX8951),producing the targeted therapy ADC.The antitumor activities of DDR1-DX8951 monotherapy or DDR1-DX8951 plus pembrolizumab were assessed in TNBC mouse models.DDR1-DX8951 can specifically target DDR1,be quickly internalized by TNBC cells,and reduce the viability of TNBC cells in vitro.The potent antitumor activity of DDR1-DX8951 was revealed in TNBC xenograft models.Importantly,our investigation demonstrated that DDR1-DX8951 plus pembrolizumab not only revealed the inhibitory efficacy on tumor growth and metastasis but also played an important role in improving the immunosuppressive tumor microenvironment(TME)of TNBC.Taken together,this investigation provides justification for large-sample studies to further assess the safety and efficacy of DDR1-DX8951 plus pembrolizumab for TNBC clinical trials.
基金supported by the Major Science and Technology Special Project of Gansu Province(24ZDFA002)the National Natural Science Foundation of China(82060459)+1 种基金the Key Research and Development Program of Gansu Province(23YFFA0007)the Joint Research Fund of Gansu Province(23JRRA1511)。
文摘Given the critical shortage of antibody-drug conjugates(ADCs)for bladder cancer(BCa),we developed a novel FGFR3-targeted ADC,LZU-WZLYFG001,composed of a humanized anti-FGFR3 IgG1 monoclonal antibody,a cleavable GGFG linker,and the payload DXD.The antibody was engineered in 293 cells and conjugated via thiol-based chemistry,achieving a drug-to-antibody ratio(DAR)of eight.Comprehensive preclinical assessments,including in vitro and in vivo studies using BCa cells,organoids,cell-derived xenograft and patient-derived xenograft(PDX)models,were conducted to evaluate efficacy,targeting ability,mechanism,safety and tissue distribution.LZU-WZLYFG001 demonstrated high purity,targeting specificity and low endotoxin levels,and it significantly inhibited BCa cell proliferation,migration and invasion at nanomolar concentrations,with efficacy strongly associated with FGFR3 expression levels.Mechanistic studies showed binding to FGFR3,internalization and lysosomal release of LZU-WZLYFG001.In organoid and xenograft models,LZU-WZLYFG001 exhibited superior efficacy compared with the gemcitabine+cisplatin(GC)regimen,particularly in GC-resistant PDX tumors,while also showing robust 3D penetration,a bystander effect,and no significant short-term toxicity.
文摘Metastatic urothelial carcinoma(mUC)is a challenging malignancy with historically limited treatment options.Advances in understanding its biology have enabled the development of innovative therapies,including immune checkpoint inhibitors and antibody-drug conjugates(ADCs).ADCs,such as enfortumab vedotin,sacituzumab govitecan,and trastuzumab deruxtecan,represent transformative advancements,offering targeted delivery of cytotoxic agents.This review highlights the evolving role of ADCs in mUC,examining their mechanisms,clinical efficacy,patient selection criteria,genetic insights,and future directions in personalized treatment strategies.
基金supported by the National Key Research and Development Program of China‘Precision Medicine Research’(Grant No.2017YFC0908602)the State Key Program of National Natural Science of China(Grant No.81430081)National Key R&D Program of China(No.2017YFE0102200)。
文摘Limited clinical application of antibody-drug conjugates(ADCs)targeting tumor associated antigens(TAAs)is usually caused by on-target off-tumor side effect.Tumor-specific mutant antigens(TSMAs)only expressed in tumor cells which are ideal targets for ADCs.In addition,intracellular somatic mutant proteins can be presented on the cell surface by human leukocyte antigen class I(HLA I)molecules forming tumor-specific peptide/HLA I complexes.KRAS G12 V mutation frequently occurred in varied cancer and was verified as a promising target for cancer therapy.In this study,we generated two TCR-mimic antibodydrug conjugates(TCRm-ADCs),2E8-MMAE and 2 A5-MMAE,targeting KRAS G12 V/HLAA*0201 complex,which mediated specific antitumor activity in vitro and in vivo without obvious toxicity.Our findings are the first time validate the strategy of TCRm-ADCs targeting intracellular TSMAs,which improves the safety of antibody-based drugs and provides novel strategy for precision medicine in cancer therapy.
文摘The past few years have witnessed enormous progresses in the development of antibody-drug conjugates(ADCs).Consequently,comprehensive analysis of ADCs in biological systems is critical in supporting discovery,development and evaluation of these agents.Liquid chromatography-mass spectrometry(LC-MS)has eme rged as a promising and versatile tool for ADC analysis across a wide range of scenarios,owing to its multiplexing ability,rapid method development,as well as the capability of analyzing a variety of targets ranging from small-molecule payloads to the intact protein with a high,molecular resolution.However,despite this tremendous potential,challenges persist due to the high complexity in both the ADC molecules and the related biological systems.This review summarizes the up-to-date LC-MS-based strategies in ADC analysis and discusses the challenges and opportunities in this rapidly-evolving field.
基金supported by Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine at Shanghai Tech University。
文摘Self-immolative linkers have been widely used to construct prodrugs to improve their efficacy and safety.In this study,we report the use of phenoxysilyl linker as a self-immolative unit to prepare antibody-drug conjugates(ADCs).Phenoxysily based ADC Ate-PPS-CA4 was prepared and its release was systematically investigated by mass spectrometry.Biological evaluation showed that Ate-PPS-CA4 displayed the ability to target delivery and self-immolative release the active payload CA4 on PD-L1 positive cells MDA-MB-231.As the same with its payload CA4,it could arrest the cell cycle to the G2/M phase and induced changes in cell morphology at the dose of its IC_(50).The development of this linker with novel drug release mechanisms will expand the methodology to construct ADCs,especially for non-internalizing ADCs by extracellular cleavage.
文摘Over the past several decades, there has been a significant surge in the development of Antibody-Drug Conjugates (ADCs). Designing an ideal ADC presents a multifaceted challenge, requiring the precise orchestration of various elements such as antigens, antibodies, linkers, and payloads. While ADCs aim to target tumor cells specifically, several antigens can also be found in regular tissues, potentially compromising the specificity of ADCs in therapeutic applications. The complexity extends to antibody selection, necessitating effective targeting of the desired antigen and ensuring compatibility with linkers for effective payload delivery. Additionally, the linker and payload combination are critical for the ADC’s therapeutic efficiency, balancing stability in circulation and timely payload release upon target binding. ADC doses must be safe for normal tissues while ensuring the released payloads are effective. The success of ADCs is attributed to their unmatched efficacy compared to traditional chemotherapy agents. The current research article aims to provide a technical review of Antibody-Drug Conjugates (ADCs) for cancer therapies. A brief discussion on the basics of ADCs, regulatory approach, overview, and technical complexities for quantification is presented. This review also summarizes recently approved ADCs and introduces the concepts of antibodies, linkers, and payloads. The article also outlines cancer-specific ADCs currently in late-stage clinical trials for cancer treatment.
基金supported by the National Natural Science Foundation of China(82403929,32471290,82203620)Natural Science Foundation of Zhejiang Province(LQ24H160007,2025C02114)+2 种基金China Postdoctoral Science Foundation(2022M722766)Postdoctoral Fellowship Program of CPSF(GZB20230642)Research and Innovation Team Project for Scientific Breakthroughs at Shanxi Bethune Hospital(2024AOXIANG04)。
文摘Gynecological cancer poses a serious threat to women's health.Despite significant advances in immunotherapy and targeted therapeutic strategies for gynecological cancers,substantial challenges persist,including limited response rates,inevitable resistance,and adverse effects.In recent years,a milestone in gynecological cancer therapy has been the approval of antibody-drug conjugates(ADCs).In this review,we provide a comprehensive overview of the structural features,mechanisms of action,and molecular characteristics of ADCs that have been approved and are currently under development.Their clinical applications and associated challenges have also been highlighted.Finally,we discuss the prospects of ADCs in the treatment of gynecological cancers.
基金supported by grants from the National Natural Science Foundation of China(82473937)Zhejiang Plan for the Special Support for Top-notch Talents of China(2022R52029)。
文摘Pancreatic cancer,mainly pancreatic ductal adenocarcinoma(PDAC),is aggressive with poor prognosis.Because its clinical manifestations appear at advanced stages,only less than 20%of patients with PDAC can undergo radical surgery.Chemotherapy,with strong toxic side effects,remains the main therapy.Therefore,developing more effective strategies for PDAC is warranted.Because of its heterogeneity and highly immunosuppressive tumor microenvironment(TME),the discovery of new drug targets and development of new therapeutic modalities for PDAC remain difficult.Antibody-drug conjugates(ADCs)—which have demonstrated efficacy against various types of cancers—improve the antitumor effects of a drug by enhancing tumor targeting,reducing toxic side effects,and increasing TME interactions via antigen presentation regulation and immunosuppressive cell inhibition.Here,we summarized the effects of ADCs on TME of PDAC,as well as the future research prospects.
基金supported by the UCSI University under the Research Excellence and Innovation Grant(REIG)(grant numbers:REIG-FAS-2023/006,REIG-FAS-2024/001).
文摘Antibody-drug conjugates(ADCs)represent a promising approach in targeted cancer therapy,combining the tar-geted precision of antibodies with the potency of cytotoxic payloads to selectively target tumour cell whilst min-imising off-target effects.This review provides a comprehensive analysis of ADCs,encompassing their structural components,mechanisms of action,and clinical applications.It also examines recent technological advancements,particularly in antibody engineering and linker design,aimed at enhancing therapeutic efficacy and safety.The current clinical landscape is outlined,highlighting approved ADCs and promising candidates in clinical trials,while also addressing key challenges such as stability,half-life,and systemic toxicity.This review is based on an extensive literature survey from major databases such as Scopus and Web of Science,with a focus on keywords like“antibody-drug conjugates”,“ADC advancements”,and“next-generation ADC technologies”.By integrating insights from both preclinical and clinical perspectives,we highlight the transformative potential of ADCs in advancing modern cancer therapy.
基金the National Natural Science Foundation of China(32400779)the National Postdoctoral Program for Innovative Talents(Bx20220189)the Fundamental Research Funds for the Central Universities(20720220006).
文摘Antibody-drug conjugates(ADCs)represent a promising class of targeted cancer therapeutics that combine the specificity of monoclonal antibodies with the potency of cytotoxic payloads.Despite their therapeutic potential,the use of ADCs faces significant challenges,including off/on-target toxicity and resistance development.This review examines the current landscape of ADC development,focusing on the critical aspects of target selection and antibody engineering.We discuss strategies to increase ADC efficacy and safety,including multitarget approaches,pH-dependent antibodies,and masked peptide technologies.The importance of comprehensive antigen expression profiling in both tumor and normal tissues is emphasized,highlighting the role of advanced technologies,such as single-cell sequencing and artificial intelligence,in optimizing target selection.Furthermore,we explore combina-tion therapies and innovations in linker-payload chemistry,which may provide approaches for expanding the ther-apeutic window of ADCs.These advances pave the way for the development of more precise and effective cancer treatments,potentially extending ADC applications beyond oncology.
基金the Project of China-Japan Joint International Laboratory of Advanced Drug Delivery System Research and Translation of Liaoning Province(No.2024JH2/102100007)the open fund of National Key Laboratory of Advanced DrugFormulations for Overcoming Delivery Barriers(No.2024-KFB-003)+1 种基金the National Natural Science Foundation of China(No.82104109)Scientific Research Project of Liaoning Department of Education(No.LJ212410163045).
文摘Cancer is the second leading cause of death globally.Its treatment remains a major challenge due to the disease's complexity,heterogeneity,and adaptive nature.Among the array of available treatments,targeted therapy emerges as a paramount approach to address this substantial unmet clinical need,owing to its precise tumor targeting capabilities and potential for mitigating tumor progression risks.Drug conjugates are in high demand for targeted therapy due to their unique ligand specificity and potent cytotoxicity,thereby significantly enhancing therapeutic efficacy and reducing the incidence of adverse effects.Therefore,as a burgeoning field in biomedical research,it is timely to outline the latest advances in drug conjugates-driven cancer treatment.Herein,we aim to present the emerging breakthroughs in this exciting field at the intersection of target ligands,linkers,payloads,and cancer treatments.This review focuses on several drug conjugates-related strategies,including antibody-drug conjugates(ADCs),peptide-drug conjugates(PDCs),small molecule-drug conjugates(SMDCs),aptamer-drug conjugates(ApDCs)and radionuclide-drug conjugates(RDCs).Finally,we discuss the fundamentals behind drug conjugate-based anticancer therapeutics,along with their inherent advantages and associated challenges,as well as recent research advances.
文摘The antibody-drug conjugate （ADC）, a humanized or human monoclonal antibody conjugated with highly cytotoxic small molecules （payloads） through chemical linkers, is a novel therapeutic format and has great potential to make a paradigm shift in cancer chemother- apy. This new antibody-based molecular platform enables selective delivery of a potent cytotoxic payload to target cancer cells, resulting in improved efficacy, reduced systemic toxicity, and preferable pharmacokinetics （PK）I pharmacodynamics （PD） and biodistribution compared to traditional chemotherapy. Boosted by the successes of FDA-approved Adcetris~ and Kadcyla~, this drug class has been rapidly growing along with about 60 ADCs cur- rently in clinical trials. In this article, we briefly review molecular aspects of each component （the antibody, payload, and linker） of ADCs, and then mainly discuss traditional and new technologies of the conjugation and linker chemistries for successful construction of clini- cally effective ADCs. Current efforts in the conjugation and linker chemistries will provide greater insights into molecular design and strategies for clinically effective ADCs from medicinal chemistry and pharmacology standpoints. The development of site-specific conjuga- tion methodologies for constructing homogeneous ADCs is an especially promising path to improving ADC design, which will open the way for novel cancer therapeutics.
基金funded by the Chinese National Natural Science Foundation(Grant Nos.81872736 and 81903451)the China Postdoctoral Science Foundation(Grant No.2019M664015)。
文摘Antibody-drug conjugates(ADCs)are gradually revolutionizing clinical cancer therapy.The antibody-drug conjugate linker molecule determines both the efficacy and the adverse effects,and so has a major influence on the fate of ADCs.An ideal linker should be stable in the circulatory system and release the cytotoxic payload specifically in the tumor.However,existing linkers often release payloads nonspecifically and inevitably lead to off-target toxicity.This defect is becoming an increasingly important factor that restricts the development of ADCs.The pursuit of ADCs with optimal therapeutic windows has resulted in remarkable progress in the discovery and development of novel linkers.The present review summarizes the advance of the chemical trigger,linker-antibody attachment and linker-payload attachment over the last 5 years,and describes the ADMET properties of ADCs.This work also helps clarify future developmental directions for the linkers.
基金the National Natural Science Foundation of China(82072916)the 2018 Shanghai Youth Excellent Academic Leader,the Fudan ZHUOSHI Project,Chinese Young Breast Experts Research project(CYBER-2021-A01).
文摘Antibody-drug conjugates(ADCs)are a rapidly developing therapeutic approach in cancer treatment that has shown remarkable activity in breast cancer.Currently,there are two ADCs approved for the treatment of human epidermal growth factor receptor 2-positive breast cancer,one for triple-negative breast cancer,and multiple investigational ADCs in clinical trials.However,drug resistance has been noticed in clinical use,especially in trastuzumab emtansine.Here,the mechanisms of ADC resistance are summarized into four categories:antibodymediated resistance,impaired drug trafficking,disrupted lysosomal function,and payload-related resistance.To overcome or prevent resistance to ADCs,innovative development strategies and combination therapy options are being investigated.Analyzing predictive biomarkers for optimal therapy selection may also help to prevent drug resistance.
基金RemeGen Co.,LtdCAMS Innovation Fund for Medical Sciences(CIFMS),Grant/Award Number:2021-I2M-1-014。
文摘Background:Disitamab vedotin(DV;RC48-ADC)is an antibody-drug conjugate comprising a human epidermal growth factor receptor 2(HER2)-directed antibody,linker and monomethyl auristatin E.Preclinical studies have shown that DV demonstrated potent antitumor activity in preclinical models of breast,gastric,and ovarian cancers with different levels of HER2 expression.In this pooled analysis,we report the safety and efficacy of DV in patients with HER2-overexpression and HER2-low advanced breast cancer(ABC).Methods:In the phase I dose-escalation study(C001 CANCER),HER2-overexpression ABC patients received DV at doses of 0.5-2.5 mg/kg once every two weeks(Q2W)until unacceptable toxicity or progressive disease.The dose range,safety,and pharmacokinetics(PK)were determined.The phase Ib dose-range and expansion study(C003 CANCER)enrolled two cohorts:HER2-overexpression ABC patients receiving DV at doses of 1.5-2.5 mg/kg Q2W,with the recommended phase 2 dose(RP2D)determined,andHER2-lowABC patients receiving DV at doses of 2.0 mg/kg Q2W to explore the efficacy and safety of DV in HER2-low ABC.Results:Twenty-four patients with HER2-overexpression ABC in C001 CANCER,46 patients with HER2-overexpressionABCand 66 patients with HER2-low ABC in C003 CANCER were enrolled.At 2.0 mg/kg RP2D Q2W,the confirmed objective response rates were 42.9%(9/21;95%confidence interval[CI]:21.8%-66.0%)and 33.3%(22/66;95%CI:22.2%-46.0%),with median progression-free survival(PFS)of 5.7 months(95%CI:5.3-8.4 months)and 5.1 months(95%CI:4.1-6.6 months)for HER2-overexpression and HER2-low ABC,respectively.Common(≥5%)grade 3 or higher treatment-emergent adverse events included neutrophil count decreased(17.6%),gamma-glutamyl transferase increased(13.2%),asthenia(11.0%),white blood cell count decreased(9.6%),peripheral neuropathy such as hypoesthesia(5.9%)and neurotoxicity(0.7%),and pain(5.9%).Conclusion:DV demonstrated promising efficacy in HER2-overexpression and HER2-low ABC,with a favorable safety profile at 2.0 mg/kg Q2W.
基金The study was supported by the grants from the National Natural Science Foundation of China(No.81874122)the Chinese Academy of Medical Sciences(CAMS)Initiative for Innovative Medicine(No.2017-I2M-3-004)。
文摘Antibody-drug conjugates(ADCs)combine the high specificity of monoclonal antibodies with the high anti-tumor activity of small molecular cytotoxic payloads.The anti-tumor activity of ADCs is mainly achieved by the direct blocking of the receptor by monoclonal antibodies,direct action and bystander effect of cytotoxic drugs,and antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity.ADCs have been used in adjuvant therapy and rescue treatment of human epidermal receptor 2(HER2)-positive breast cancer,greatly improving the prognosis of breast cancer patients.Several ongoing clinical trials of ADC for breast cancer and other solid tumors proved the potential of ADCs will provide more promising treatment options for patients with malignant tumors.This review introduces the mechanism and latest clinical progress of ADC drugs approved for HER2-positive breast cancer to guide clinical practice and conduct research.
基金This work was supported by grants(NIH/NCI RO15R01CA237154-02)-TrotmanNIH/NCI CSHL Cancer Center Support Grant 5P30CA45508-33(Tuveson)-Trotman and Lyonsthe German Research Foundation(DFG)(PL 894/1-1)-Plenker.
文摘The ability to chemically modify monoclonal antibodies with the attachment of specific functional groups has opened up an enormous range of possibilities for the targeted treatment and diagnosis of cancer in the clinic.As the number of such antibody-based drug candidates has increased,so too has the need for more stringent and robust preclinical evaluation of their in vivo performance to maximize the likelihood that time,research effort,and money are only spent developing the most effective and promising candidate molecules for translation to the clinic.Concurrent with the development of antibody-drug conjugate(ADC)technology,several recent advances in preclinical research stand to greatly increase the experimental rigor by which promising candidate molecules can be evaluated.These include advances in preclinical tumor modeling with the development of patient-derived tumor organoid models that far better recapitulate many aspects of the human disease than conventional subcutaneous xenograft models.Such models are amenable to genetic manipulation,which will greatly improve our understanding of the relationship between ADC and antigen and stringently evaluate mechanisms of therapeutic response.Finally,tumor development is often not visible in these in vivo models.We discuss how the application of several preclinical molecular imaging techniques will greatly enhance the quality of experimental data,enabling quantitative pre-and post-treatment tumor measurements or the precise assessment of ADCs as effective diagnostics.In our opinion,when taken together,these advances in preclinical cancer research will greatly improve the identification of effective candidate ADC molecules with the best chance of clinical translation and cancer patient benefit.
文摘Human epidermal growth factor 2(HER2)-positive breast cancer(BC)represents nearly 20%of all breast tumors.Historically,these patients had ahigh rate of relapse and dismal prognosis.The advent of HER2-targeting monoclonal antibodies such astrastuzumab followed by pertuzumab had improved the prognosis of HER2-positive metastatic BC.More recently,antibody-drug conjugates(ADCs)are now reshaping the treatment paradigm of solid tumors,especially breastcancer.Tratsuzumab emtansine(T-DM1)was one of the first ADC developed in oncology and was approved forthe management of HER2-positive metastatic BC.In a head-to-head comparison,trastuzumab deruxtecan(T-DXd)defeated T-DM1 as a second-line treatment.The efficacy of ADCs is counterbalanced by the appearance ofacquired resistance to these agents.In this paper,we summarize the mechanisms of action and resistance ofT-DM1 and T-DXd,as well as their clinical efficacy.Additionally,we also discuss potential strategies for addressingresistance to ADC.
基金This study was supported by a grant from the National Natural Science Foundation of China.
文摘Monoclonal antibody-drug conjugate was applied in a clinical trial for patients with bladder cancer, Monoclonal antibody HB7A from a mouse splenocyte immunized against human bladder cancer was used as a drug carrier, The anti-cancer drug adriamycin (ADR) was bound to HB7A through a dextran (DEX) bridge to form the conjugate HB7A-DEX-ADR. The in vitro cytotoxic effect of the conjugate on BIU-87 bladder cancer cells was similar to that of free ADR and the mixture of HB7A and ADR, Seven patients with bladder cancer were given HB7A-DEX-ADR intravenously. The immunoperoxidast studies of the resected specimens showed that HB7A was localized specifically in cancer, and histological studies revealed degenerative and necrotic changes of the tumor cells, Patients receiving the conjugate did not experience serious side effects, This study suggests that immunotargeting chemotherapy with HB7A-DEX-ADR is well tolerated by patients and its cytotoxicity on tumor is substantial.
