Antibody-Drug Conjugates for the Therapy of Thoracic Malignancies

Abstract

Antibody-drug conjugates (ADCs) are a novel class of therapeutic agents incorporating both target-specific monoclonal antibodies and cytotoxic small molecules via a chemical linker. They were first introduced into the clinic for the treatment of advanced hematologic malignancies. The only approved ADC for solid tumors targets erb-b2 receptor tyrosine kinase (HER2), a validated antigen in breast cancer. Many ADCs are under active investigation for various types of solid tumors. In this article, we review the literature from several perspectives including the design, pharmacology, and mechanism-based toxicities of antibodydrug conjugates. We then discuss ADCs currently in clinical development for thoracic malignancies. MethodsA systematic analysis of the literature was conducted on antibody-drug conjugates (ADCs) in thoracic malignancies by performing a medical subject headings search in PubMed using the term antibody-drug conjugates combined with lung cancer or mesothelioma and therapeutics.

Antibody-drug conjugates in clinical trials for lymphoid malignancies and multiple myeloma

“…The payloads used in ADCs are selected small molecules with high potency and proper hydropholicity [20,21]. Another important parameter is drug-antibody ratio (DAR), which is defined as the average number of payload molecules attached to a single mAb.…”

The promising role of antibody drug conjugate in cancer therapy: Combining targeting ability with cytotoxicity effectively

“…51,145 A confirmation phase 3 EV-301 trial exploring EVs compared with chemotherapy is ongoing. 4.2.2 | Newly diagnosed advanced cancer First-line application of TDM-1 was evaluated for advanced HER2-positive breast cancer patients, wherein the phase 3 MARIANNE trial compared T-DM1 plus pertuzumab and T-DM1 monotherapy with trastuzumab plus taxane (control group). Results showed that T-DM1 with or without pertuzumab had similar efficacy with the control group (median PFS: 15.2 months vs. 14.1 months vs. 13.7 months; response rate: 64.2% vs. 59.7% vs. 67.9%; median response duration: 21.2 months vs. 20.7 months vs. 12.5 months), while there was a lower rate of AEs over grade 3 (46.2% vs. 45.4% vs. 54.1%).…”

“…13,174 The conjugation strategy affects the homogeneity of the drug-to-antibody ratio (DAR, the average number of cytotoxic molecules attached to each antibody), the release time of cytotoxic payloads, and off-target toxicity. 4 Compared with traditional nonspecific conjugation, site-specific conjugations could increase the homogeneity, stability, pharmacokinetics, and decrease toxicity. [175][176][177] However, considering the inefficient chemistry and immunogenicity, new technologies are still under development for a better controlled DAR and homogeneity of ADC.…”

“…Antibody drug conjugate is a conjugate composed of three fundamental components, namely, monoclonal antibodies that target‐specific tumor antigens, high‐potency small molecular cytotoxic payloads, and stable linkers. 4 The basic characteristics of each component are shown in Figure 1 .…”

“…Current hypothetic mechanisms include decreased penetration caused by tumor microenvironment changes, downregulation of antigens, deficiencies in pathways of internalization, and resistance to payloads. 4 , 26 Some payloads might be transported by ATP‐binding cassette transporter proteins such as multidrug resistance protein 1 (MDR1), which induces active efflux of the payload and leads to drug resistance. 181 Studies on resistance mechanisms could lead to promising directions for further optimization of ADCs.…”