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.