Perspectives on the development of antibody-drug conjugates targeting ROR1 for hematological and solid cancers

Drug Conjugates ◽

Solid Malignancies ◽

Selective Delivery ◽

And Performance ◽

Antibody Drug ◽

Made In

Abstract Antibody–drug conjugates (ADCs) are targeted therapeutics generated by conjugation of cytotoxic small molecules to monoclonal antibodies (mAbs) via chemical linkers. Due to their selective delivery of toxic payloads to antigen-positive cancer cells, ADCs demonstrate wider therapeutic indexes compared to conventional chemotherapy. After decades of intensive research and development, significant advances have been made in the field, leading to a total of ten FDA-approved ADCs to treat cancer patients. Currently, ~ 80 ADCs targeting different antigens are under clinical evaluation for treatment of either hematological or solid malignancies. Notably, 3 ADCs targeting the same oncofetal protein, ROR1, have attracted considerable attention when they were acquired or licensed successively in the fourth quarter of 2020 by 3 major pharmaceutical companies. Apparently, ROR1 has emerged as an attractive target for cancer therapy. Since all the components of ADCs, including the antibody, linker, and payload, as well as the conjugation method, play critical roles in ADC’s efficacy and performance, their choice and combination will determine how far they can be advanced. This review summarizes the design and development of current anti-ROR1 ADCs and highlights an emerging trend to target ROR1 for cancer therapy.

Antibody-drug conjugates for cancer therapy: The technological and regulatory challenges of developing drug-biologic hybrids

Biologicals ◽

10.1016/j.biologicals.2015.05.006 ◽

2015 ◽

Vol 43 (5) ◽

pp. 318-332 ◽

Cited By ~ 35

Author(s):

Gregory S. Hamilton

Keyword(s):

Cancer Therapy ◽

Drug Conjugates ◽

Antibody Drug ◽

Regulatory Challenges

Antibody-Drug Conjugates for Cancer Therapy: Chemistry to Clinical Implications

Pharmaceuticals ◽

10.3390/ph11020032 ◽

2018 ◽

Vol 11 (2) ◽

pp. 32 ◽

Cited By ~ 69

Author(s):

◽

...

Keyword(s):

Cancer Therapy ◽

Clinical Implications ◽

Drug Conjugates ◽

Catalytic Cleavage of Disulfide Bonds in Small Molecules and Linkers of Antibody–Drug Conjugates

Drug Metabolism and Disposition ◽

10.1124/dmd.118.086132 ◽

2019 ◽

Vol 47 (10) ◽

pp. 1156-1163 ◽

Cited By ~ 6

Author(s):

Donglu Zhang ◽

Aimee Fourie-O’Donohue ◽

Peter S. Dragovich ◽

Thomas H. Pillow ◽

Jack D. Sadowsky ◽

...

Keyword(s):

Small Molecules ◽

Disulfide Bonds ◽

Drug Conjugates ◽

Catalytic Cleavage ◽

The Pharmaceutical Industry in 2019. An Analysis of FDA Drug Approvals from the Perspective of Molecules

Molecules ◽

10.3390/molecules25030745 ◽

2020 ◽

Vol 25 (3) ◽

pp. 745 ◽

Cited By ~ 23

Author(s):

Beatriz G. de la Torre ◽

Fernando Albericio

Keyword(s):

Natural Products ◽

Pharmaceutical Industry ◽

Small Molecules ◽

Chemical Structure ◽

New Drugs ◽

Drug Conjugates ◽

The Us ◽

New Chemical Entities ◽

During 2019, the US Food and Drug Administration (FDA) approved 48 new drugs (38 New Chemical Entities and 10 Biologics). Although this figure is slightly lower than that registered in 2018 (59 divided between 42 New Chemical Entities and 17 Biologics), a year that broke a record with respect to new drugs approved by this agency, it builds on the trend initiated in 2017, when 46 drugs were approved. Of note, three antibody drug conjugates, three peptides, and two oligonucleotides were approved in 2019. This report analyzes the 48 new drugs of the class of 2019 from a strictly chemical perspective. The classification, which was carried out on the basis of chemical structure, includes the following: Biologics (antibody drug conjugates, antibodies, and proteins); TIDES (peptide and oligonucleotides); drug combinations; natural products; and small molecules.

Potent antibody drug conjugates for cancer therapy

Current Opinion in Chemical Biology ◽

10.1016/j.cbpa.2009.03.023 ◽

2009 ◽

Vol 13 (3) ◽

pp. 235-244 ◽

Cited By ~ 266

Author(s):

Peter D Senter

Keyword(s):

Cancer Therapy ◽

Drug Conjugates ◽

Monoclonal Antibody Drug Conjugates for Cancer Therapy

Prodrugs - Biotechnology: Pharmaceutical Aspects ◽

10.1007/978-0-387-49785-3_14 ◽

2007 ◽

pp. 507-524 ◽

Cited By ~ 1

Author(s):

Peter D. Senter ◽

Damon L. Meyer

Keyword(s):

Monoclonal Antibody ◽

Cancer Therapy ◽

Drug Conjugates ◽

Antibody–Drug Conjugates for Cancer Therapy

Molecules ◽

10.3390/molecules25204764 ◽

2020 ◽

Vol 25 (20) ◽

pp. 4764

Author(s):

Umbreen Hafeez ◽

Sagun Parakh ◽

Hui K. Gan ◽

Andrew M. Scott

Keyword(s):

Monoclonal Antibody ◽

Molecular Imaging ◽

Cancer Therapy ◽

Normal Tissue ◽

Clinical Development ◽

Drug Conjugates ◽

Novel Drugs ◽

Antibody–drug conjugates (ADCs) are novel drugs that exploit the specificity of a monoclonal antibody (mAb) to reach target antigens expressed on cancer cells for the delivery of a potent cytotoxic payload. ADCs provide a unique opportunity to deliver drugs to tumor cells while minimizing toxicity to normal tissue, achieving wider therapeutic windows and enhanced pharmacokinetic/pharmacodynamic properties. To date, nine ADCs have been approved by the FDA and more than 80 ADCs are under clinical development worldwide. In this paper, we provide an overview of the biology and chemistry of each component of ADC design. We briefly discuss the clinical experience with approved ADCs and the various pathways involved in ADC resistance. We conclude with perspectives about the future development of the next generations of ADCs, including the role of molecular imaging in drug development.