Drug conjugates for the treatment of lung cancer: from drug discovery to clinical practice

Abstract

A drug conjugate consists of a cytotoxic drug bound via a linker to a targeted ligand, allowing the targeted delivery of the drug to one or more tumor sites. This approach simultaneously reduces drug toxicity and increases efficacy, with a powerful combination of efficient killing and precise targeting. Antibody‒drug conjugates (ADCs) are the best-known type of drug conjugate, combining the specificity of antibodies with the cytotoxicity of chemotherapeutic drugs to reduce adverse reactions by preferentially targeting the payload to the tumor. The structure of ADCs has also provided inspiration for the development of additional drug conjugates. In recent years, drug conjugates such as ADCs, peptide‒drug conjugates (PDCs) and radionuclide drug conjugates (RDCs) have been approved by the Food and Drug Administration (FDA). The scope and application of drug conjugates have been expanding, including combination therapy and precise drug delivery, and a variety of new conjugation technology concepts have emerged. Additionally, new conjugation technology-based drugs have been developed in industry. In addition to chemotherapy, targeted therapy and immunotherapy, drug conjugate therapy has undergone continuous development and made significant progress in treating lung cancer in recent years, offering a promising strategy for the treatment of this disease. In this review, we discuss recent advances in the use of drug conjugates for lung cancer treatment, including structure-based drug design, mechanisms of action, clinical trials, and side effects. Furthermore, challenges, potential approaches and future prospects are presented.

Keywords: Clinical practice; Drug conjugates; Drug discovery; Lung cancer.

Fig. 1

The history of drug conjugates. A History of ADC development. B History of peptide development. C History of nuclear medicine development. ADC antibody‒drug conjugate, FDA Food and Drug Administration, RDC radionuclide drug conjugate

Fig. 2

Standard-of-care treatments and combination therapy involving ADCs in lung cancer. ADC antibody‒drug conjugate, VEGFR vascular endothelial growth factor receptor

Fig. 3

Mechanism of antibody–drug conjugates. ADCs bind to target antigens to form complexes, which are internalized by endocytosis. Linker cleavage leads to the release of cytotoxic drugs. ADC antibody‒drug conjugate

Fig. 4

Chemical structures of representative antibody‒drug conjugates (ADCs) in clinical trials for lung cancer treatment

Fig. 4

Chemical structures of representative antibody‒drug conjugates (ADCs) in clinical trials for lung cancer treatment

Fig. 5

Chemical structures of representative peptide‒drug conjugates (PDCs) in clinical trials for lung cancer treatment

Fig. 5

Chemical structures of representative peptide‒drug conjugates (PDCs) in clinical trials for lung cancer treatment

Fig. 6

Drug conjugates in trials for lung cancer treatment. ADCs antibody‒drug conjugates, PDCs peptide‒drug conjugates, RDCs radionuclide drug conjugates, SMDCs small molecule–drug conjugates, ACCs antibody–cell conjugates, ISACs immune-stimulating antibody conjugates, VDCs virus–like drug conjugates, ADeCs antibody–degrader conjugates

Fig. 7

Chemical structures of other representative drug conjugates in clinical trials for lung cancer treatment

Fig. 8

Measures to address the difficulties associated with drug conjugate development and application. DAR drug-to-antibody ratio