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Current Research Progress In Antibody-Drug Conjugates

Antibody-drug conjugates (ADCs) are a new class of highly potent oncology therapeutics for the treatment of people with cancer. They could be divided into three main structural units: the antibody; the cytotoxic agent (drug); and the linker. Discovery of ADCs bridged the gap between the cytotoxic drug and antibody, creating highly potent anticancer agents for targeted cancer therapy. There has been a significant increase in the number of clinical trials with anticancer ADCs and the following is a list of ADCs in clinical trials.

Clinical Trial Stage ADC name Antibody/Linker Cytotoxic drugs Cancer types Antigen targeted
Phase I ASG-22ME Hu IgG1/valine-citrulline (V.C) MMAE Urothelial and other malignant solid tumors Nectin-4
SAR566658 Hz IgG1/DS6 disulfide Maytansinoid Malignant neoplasm, triplenegative breast cancer CA6
BAY 94-9343 H IgG1/disulfide, HuIgG1/SPDB Maytansinoid, (DM4) Mesothelin-positive solid tumors Mesothelin
IMGN388 IgG1/disulfide Maytansinoid Solid tumors Integrin αv
BIIB015 IgG1/disulfide Maytansinoid Anti-Cripto, refractory solid tumors Cripto-1
SGN-75 Anti D70/dipeptide Auristatin Renal cell carcinoma CD70
AGS-22M6E Anti-Nectin fully human IgG/dipeptide Auristatin Malignant solid tumors Nectin4
IMGN529 K7153A humanized IgG1/ thioether Maytansinoid B cell malignancies CD37
AMG595 Anti-EGFRvIII fully human IgG1/thioether Maytansinoid Glioblastoma EGFRvIII
RG7593/DCDT2980S Hz IgG1/valine-citrulline MMAE NHL CD22
SAR566658 Hu IgG1/SPDB Maytansine (DM4) Solid tumors CA6
Labestuzumab-SN-38 HzIgG1/phenylalanine-lysine SN38 Colorectal cancer CD66e/CEACAM5
AGS-16C3F Hu IgG2/maleimidocaproyl MMAF Renal cell carcinoma ENPP3
SGN-CD33A Hz PDB dimer AML CD33
SGN-CD19A Hz IgG1/maleimidocaproyl MMAF B cell lymphoma CD19
SGN-LIV1A Hz IgG1/V.C MMAE Metastatic breast cancer LIV-1
RG7596 Hz IgG1/V.C MMAE NHL CD79b
ASG-5ME Hu IgG2/V.C MMAE Pancreatic, gastric, an prostate cancers SLC44A4
BAY 79-4620 Hu IgG1/V.C MMAE Advanced solid tumors CA-IX
AGS-67E Hu IgG2/V.C MMAE Lymphoid malignancies, leukemia CD37
AMG-172 Hu IgG1/MCC Maytansine (DM1) Clear cell renal cell carcinoma, renal cell adenocarcinoma and carcinoma CD27L
AGS15E Hu IgG2/[cleavable] MMAE Metastatic urothelial cancer SLITRK6
GSK2857916 Hz IgG1/maleimidocaproyl MMAF Multiple myeloma BCMA
IMGN289 Humanized Anti-EGFR Antibody, J2898A/SMCC Maytansine (DM1) EGFR-positive solid tumors EGFR
AMG 595 Hu anti-EGFRvIII specific IgG1 antibody/SMCC Maytansine DM1 Advanced malignant glioma,

anaplastic astrocytomas, glioblastoma multiforme

EGFRvIII
IMGN242 (huC242-DM4) Humanized IgG1/huC242 disulfide Maytansinoid Solid tumors CanAg
Phase I/II Immunomedics (IMMU)-110 (hLL1-DOX) Milatuzumab hydrazone Doxorubicin Multiple myeloma CD74
Lorvotuzumab mertansine (IMGN901) Humanized IgG1/huC242 disulfide Maytansinoid Multiple myeloma, solid tumors CD56
IMMU-132 Hz IgG1/CL2A CPT-11 SN38 Colorectal cancer, gastric

adenocarcinoma, esophageal cancer, hepatocellular carcinoma

TROP-2
Milatuzumab doxorubicin Hz IgG1/hydrazone Doxorubicin Multiple myeloma CD74
HuMax® -TF Hu IgG1/V.C MMAE Solid tumors Tissue factor
Phase II SAR3419 (huB4-DM4) huB4/humanized IgG1 disulfide, Hz IgG1/SPDB DM4 B cell NHL CD19
BT062 ChIgG4/SPDB, anti-CD138 chimeric IgG4 disulfide DM4 Multiple myeloma CD138, Syndecan1
Glembatumumab vedotin (CDX-011) Hu IgG2/valine-citrullin, anti-CR011 dipeptide MMAE Breast cancer melanoma, squamous cell carcinoma of lung gpNMB
Anti-PSMA ADC Hu IgG1/V.C MMAE Prostate cancer PSMA
MLN0264 Hu IgG1/V.C MMAE Gastrointestinal malignancies Guanylyl cyclase C
Lorvotuzumab mertansine Hz IgG1/SPP DM1 Solid tumors CD56
PSMA ADC Anti-PSMA fully human IgG1/dipeptide Auristatin Metastatic, hormone-refractory prostate cancer PSMA
Phase III Inotuzumab ozogamicin (CMC 544) Humanized IgG4/G5/44 hydrazone Calicheamicin B- cell lymphomas, NHL CD22
FDA Approved Gemtuzumab ozogamicin (mylotarg®), Now terminated Hu IgG4/hydrazone Calicheamicin AML CD33
Trastuzumab-emtansine (Kadcyla®) HzIgG1 trastuzumab/thioether DM1 Metastatic breast cancer HER2
Brentuximab vedotin (Adcetris®) Ch IgG1/V.C MMAE Hodgkin’s lymphoma CD30
Terminated LOP628 HzIgG1/(noncleavable) Maytansine AML/C-Kit-positive solid tumors cKit

 

Extensive research is ongoing to improve all the components of ADCs that can enhance their selectivity and therapeutic efficacy against tumors. Immunohistology, circulating tumor cells and imaging techniques have been used to determine the patient population likely to respond to ADC therapy. Protein scaffolds, which have high binding affinity to antigen, have been utilized as an approach to increase the binding affinity of ADCs, With advances in the development of ADCs , we believe that more and more ADCs will be used as safe and efficacious cancer medicine.

 

References
1. Sau S, Alsaab HO, Kashaw SK, Tatiparti K, Iyer AK.Advances in antibody-drug conjugates: A new era of targeted cancer therapy.Drug Discov Today. 2017 Jun 13. pii: S1359-6446(17)30078-8.

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