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antibody-drug conjugates： recent advances in conjugation and linker chemistries

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Protein & Cell 2018年第1期9卷 33-46页

作者： Kyoji Tsuchikama Zhiqiang An Texas Therapeutics Institute The Brown Foundation Institute of Molecular Medicine The University of Texas Health ScienceCenter at Houston Houston TX 77054 USA

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.

关键词： antibody-drug conjugates cancer,chemotherapy conjugation linker site-specific conjugation

The ABC of ADCs (antibody-drug conjugates): A Comprehensive Review of Technical, Regulatory, and Clinical Challenges

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Advances in Chemical Engineering and Science 2023年第4期13卷 363-381页

作者： Kishore Kumar Hotha Veranova Devens MA USA

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.

关键词： antibody-drug conjugates Cancer Therapy Payload Linker Conjugation Chemistry antibody Analytical Development Manufacturing of ADCs

Enzyme-linked immunosorbent assays for quantification of MMAE-conjugated ADCs and total antibodies in cynomolgus monkey sera

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Journal of Pharmaceutical Analysis 2022年第4期12卷 645-652页

作者： Min Pei Tingting Liu Lu Ouyang Jianhua Sun Xiaojie Deng Xiaomin Sun Wei Wu Peng Huang Yi-Li Chen Xiaorong Tan Xiaoyue Liu Peng Zhu Yongzhen Liu Deheng Wang Junliang Wu Qi Wang Guifeng Wang Likun Gong Qiuping Qin Chunhe Wang Biotherapeutics Discovery Research Center Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China School of Pharmacy University of Chinese Academy of SciencesBeijing100049China Center for drug Safety Evaluation and Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China Research and Development Center Dartsbio Pharmaceuticals Ltd.ZhongshanGuangdong528400China Zhongshan Institute for drug Discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshanGuangdong528400China School of Pharmacy Shanghai Engineering Research Center of ImmunotherapeuticsFudan UniversityShanghai201203China

antibody-drug conjugates(ADCs)are commonly heterogeneous and require extensive assessment of exposure-efficacy and exposure-safety relationships in preclinical and clinical studies.In this study,we report the generation of a monoclonal antibody against monomethyl auristatin E(MMAE)and the development,validation,and application of sensitive and high-throughput enzyme-linked immunosorbent assays(ELISA)to measure the concentrations of MMAE-conjugated ADCs and total antibodies(tAb,antibodies in ADC plus unconjugated antibodies)in cynomolgus monkey sera.These assays were successfully applied to in vitro plasma stability and pharmacokinetic(PK)studies of SMADC001,an MMAE-conjugated ADC against trophoblast cell surface antigen 2(TROP-2).The plasma stability of SMADC001 was better than that of similar ADCs coupled with PEG4-Val-Cit,Lys(m-dPEG24)-Cit,and Val-Cit linkers.The developed ELISA methods for the calibration standards of ADC and tAb revealed a correlation between serum concentrations and the OD450 values,with R2 at 1.000,and the dynamic range was 0.3-35.0 ng/mL and 0.2-22.0 ng/mL,respectively;the intra-and inter-assay accuracy bias%ranged from -12.2% to -5.2%,precision ranged from -12.4% to -1.4%,and the relative standard deviation(RSD)was less than 6.6% and 8.7%,respectively.The total error was less than 20.4%.The development and validation steps of these two assays met the acceptance criteria for all addressed validation parameters,which suggested that these can be applied to quantify MMAE-conjugated ADCs,as well as in PK studies.Furthermore,these assays can be easily adopted for development of other similar immunoassays.

关键词： Monomethyl auristatin E antibody-drug conjugates Pharmacokinetics Trophoblast cell surface antigen 2

Improving HER2 testing reproducibility in HER2-low breast cancer

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Cancer drug Resistance 2022年第4期5卷 882-888页

作者： Elham Sajjadi Konstantinos Venetis Mariia Ivanova Nicola Fusco Division of Pathology IEOEuropean Institute of Oncology IRCCSMilan 20141Italy Department of Oncology and Hemato-Oncology University of MilanMilan 20122Italy

HER2 is a pillar biomarker in breast cancer,and it is assessed by immunohistochemistry(IHC)using a three-tier scoring system and reflex in situ hybridization(ISH)for IHC score 2+.Novel HER2-directed antibody-drug conjugates have demonstrated significant antitumor activity in breast cancers with low levels of HER2 expression,i.e.IHC score 1+or ISH-negative IHC score 2+.Both primary and acquired resistance to anti-HER2 therapies remains a challenge in the treatment of breast cancers according to the HER2 positivity continuum.Thus,the ability to precisely discriminate among HER2-zero,HER2-low,and HER2-positive breast cancers is no longer a mere academic exercise.HER2 testing criteria,guidelines,and quality controls are re-gaining momentum for this new clinical need.Therefore,all preanalytical and analytical variables that might trouble the sensitivity and reproducibility of this test should be carefully considered to address all possible issues and open all possible therapeutic opportunities for breast cancer patients.

关键词： Breast cancer biomarkers HER2 HER2 low targeted therapy antibody-drug conjugates immunohistochemistry ISH

Targeting triple-negative breast cancer:A clinical perspective

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Oncology Research 2023年第3期31卷 221-238页

作者： LAZAR S.POPOVIC GORANA MATOVINA-BRKO MAJA POPOVIC KEVIN PUNIE ANA CVETANOVIC MATTEO LAMBERTINI Department of Medical Oncology Oncology Institute of VojvodinaSremska KamenicaSerbia Faculty of Medicine University of Novi SadNovi SadSerbia Department of General Medical Oncology and Multidisciplinary Breast Centre Leuven Cancer InstituteUniversity Hospitals LeuvenLeuvenBelgium Department for Oncology Medical Faculty NisUniversity of NisNisSerbia Clinic of Oncology Clinical Centre NisNisSerbia Department of Internal Medicine and Medical Sciences(DiMI) School of MedicineUniversity of GenovaGenovaItaly Department of Medical Oncology U.O.C Clinica di Oncologia MedicaIRCCS Ospedale Policlinico San MartinoGenovaItaly

Triple-negative breast cancer(TNBC)is a disease with often an aggressive course and a poor prognosis compared to other subtypes of breast cancer.TNBC accounts for approximately 10%–15%of all diagnosed breast cancer cases and represents a high unmet need in the field.Up to just a few years ago,chemotherapy was the only systemic treatment option for this subtype(1).To date,TNBC is considered a heterogeneous disease.One of the existing classifications is based on the analysis of mRNA expression in 587 TNBC cases,in which Lehman et al.proposed six subtypes of TNBC as follows:two basal-like(BL1 and BL2)subtypes,a mesenchymal(M)subtype,a mesenchymal stem-like(MSL)subtype,an immunomodulatory(IM)subtype,and a luminal androgen receptor(LAR)subtype(2).Later studies have demonstrated that the IM and MSL subtypes do not correlate with independent subtypes but reflect background expression by dense infiltration of tumor-infiltrating lymphocytes(TILs)or stromal cells.According to this finding,the classification of TNBC has been revised into the following four subtypes:basal 1,basal 2,LAR,and mesenchymal subtypes(3).Over the last years,several new strategies have been investigated for the treatment of patients with TNBC.Among them,immunotherapy,antibody drug conjugates,new chemotherapy agents,and targeted therapy have been and are currently being developed.The present article aims to provide an updated overview on the different treatment options that are now available or are still under investigation for patients with TNBC.

关键词： Triple-negative breast cancer Immunotherapy antibody-drug conjugates Target therapy

Bioorthogonal Prodrug–antibody conjugates for On-Target and On-Demand Chemotherapy

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CCS Chemistry 2019年第2期1卷 226-236页

作者： Feng Lin Long Chen Heng Zhang William Shu Ching Ngai Xiangmei Zeng Jian Lin Peng R.Chen Synthetic and Functional Biomolecules Center Beijing National Laboratory for Molecular SciencesCollege of Chemistry and Molecular EngineeringPeking UniversityBeijing 100871China Academy for Advanced Interdisciplinary Studies Peking UniversityBeijing 100871China Peking-Tsinghua Center for Life Sciences Peking UniversityBeijing 100871China

Current antibody–drug conjugates(ADCs)suffer from low tissue penetration and significant side effects,largely due to the permanent linkage and/or premature release of cytotoxic payloads.Herein,we developed a prodrug–antibody conjugate(ProADC)strategy by conjugating a bioorthogonal-activatable prodrug with an antibody that allowed on-target release and on-demand activation of cytotoxic drugs at a tumor site.The bioorthogonal-caged prodrug exhibited an enhanced permeability into and on-demand activation within cancer cells,while the pH-sensitive ADC linker allowed on-target release of the anticancer agent.Together,the ProADCs showed enhanced tumor penetration and alleviated side effects for use as an on-target and on-demand chemotherapy agents.

关键词： antibody-drug conjugates bioortho-gonal prodrug iEDDA reaction enhanced tumor penetration alleviated side effects

Therapeutic applications of genetic code expansion

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Synthetic and Systems Biotechnology 2018年第3期3卷 150-158页

作者： Yujia Huang Tao Liu State Key Laboratory of Natural and Biomimetic drugs School of Pharmaceutical SciencesPeking UniversityBeijing100191China

In nature,a limited,conservative set of amino acids are utilized to synthesize proteins.Genetic code expansion technique reassigns codons and incorporates noncanonical amino acids(ncAAs)through orthogonal aminoacyltRNA synthetase(aaRS)/tRNA pairs.The past decade has witnessed the rapid growth in diversity and scope for therapeutic applications of this technology.Here,we provided an update on the recent progress using genetic code expansion in the following areas:antibody-drug conjugates(ADCs),bispecific antibodies(BsAb),immunotherapies,long-lasting protein therapeutics,biosynthesized peptides,engineered viruses and cells,as well as other therapeutic related applications,where the technique was used to elucidate the mechanisms of biotherapeutics and drug targets.

关键词： Genetic code expansion Noncanonical amino acids Biotherapeutics antibody-drug conjugates Live-attenuated vaccines

Research advances and new challenges in overcoming triple-negative breast cancer

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Cancer drug Resistance 2021年第3期4卷 517-542页

作者： Yu Zong Mark Pegram Stanford Cancer Institute Stanford University School of MedicineStanfordCA 94305USA

Triple-negative breast cancer(TNBC)is a pathological term used to identify invasive breast cancers that lack expression of estrogen and progesterone receptors and do not have pathologic overexpression of the HER2 receptor or harbor ERBB2 gene amplification.TNBC includes a collection of multiple distinct disease entities based upon genomic,transcriptomic and phenotypic characterization.Despite improved clinical outcomes with the development of novel therapeutics,TNBC still yields the worst prognosis among all clinical subtypes of breast cancer.We will systematically review evidence of the genomic evolution of TNBC,as well as potential mechanisms of disease progression and treatment resistance,defined in part by advances in next-generation DNA sequencing technology(including single cell sequencing),providing a new perspective on treatment strategies,and promise to reveal new potential therapeutic targets.Moreover,we review novel therapies aimed at homologous recombination deficiency,PI3 kinase/AKT/PTEN pathway activation,androgen receptor blockade,immune checkpoint inhibition,as well as antibody-drug conjugates engaging novel cell surface targets,including recent progress in pre-clinical and clinical studies which further validate the role of targeted therapies in TNBC.Despite major advances in treatment for TNBC,including FDA approval of 2 PARP inhibitors for metastatic TNBC,the crossing of the superiority boundary in a phase 3,placebo-controlled study of adjuvant olaparib in early-stage patients with germline BRCA-mutated high-risk HER2-negative early breast cancer,the FDA approval of 2 PD-(L)1 checkpoint antibodies for metastatic TNBC,and the FDA approval of the first antibody drug conjugate for TNBC,significant challenges remain.For example,despite the dawn of immunotherapy in metastatic TNBC,durable responses are limited to a small subset of patients,definitive biomarkers for patient selection are lacking,and the Oncology drug Advisory Committee to the FDA has recently voted against approval of an anti-PD-1 ch

关键词： Triple negative breast cancer subtypes genomic evolution therapeutic targets homologous recombination deficiency antibody-drug conjugates immunotherapy tumor immune microenvironment

Immune targeted therapy for diffuse large B cell lymphoma

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Blood Science 2021年第4期3卷 136-148页

作者： Yaxin Zheng Junqi Si Tian Yuan Sa Ding Chen Tian Department of Hematology Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinChina Department of Oncology Hetian District People’s HospitalHetian 848000XinjiangChina

Diffuse large B-cell lymphoma(DLBCL),the most common subtype of non-Hodgkin lymphoma,is highly heterogeneous and invasive.Although the majority of DLBCL patients show a good response to rituximab plus cyclophosphamide,doxorubicin,vincristine,and prednisone treatment,approximately one-third of patients still have a poor prognosis.Many immune-targeted drugs,such as bispecific T-cell engagers and CAR T-cell therapy,have been proven effective for refractory and relapsed patients.This article reviews the progress of immune targeted therapy for DLBCL.

关键词： antibody-drug conjugates Checkpoint inhibitors DLBCL Monoclonal antibodies Signaling pathway inhibitors