Antibody-drug conjugates: beyond current approvals and potential future strategies

Abstract

The recent approvals for antibody-drug conjugates (ADCs) in multiple malignancies in recent years have fuelled the ongoing development of this class of drugs. These novel agents combine the benefits of high specific targeting of oncogenic cell surface antigens with the additional cell kill from high potency cytotoxic payloads, thus achieving wider therapeutic windows. This review will summarise the clinical activity of ADCs in tumour types not covered elsewhere in this issue, such as gastrointestinal (GI) and genitourinary (GU) cancers and glioblastoma (GBM). In addition to the ongoing clinical testing of existing ADCs, there is substantial preclinical and early phase testing of newer ADCs or ADC incorporating strategies. This review will provide selected insights into such future development, focusing on the development of novel ADCs against new antigen targets in the tumour microenvironment (TME) and combination of ADCs with immuno-oncology (IO) agents.

Unlocking the Potential of Bio‐Based Nitrogen‐Rich Furanic Platforms as Biomass Synthons

“…Additionally, we were interested to explore the potential of the aldehyde as a biorthogonal handle in chemical biology. Protein and antibody site‐selective modification is a powerful tool in drug development, with 11 Food and Drug Administration (FDA) approved antibody drug conjugates (ADCs) in 2022 and 80 ADCs in development [37] . The importance of obtaining well defined homogeneous bioconjugates propelled the investigation of site‐selective modification.…”

“…Protein and antibody site-selective modification is a powerful tool in drug development, with 11 Food and Drug Administration (FDA) approved antibody drug conjugates (ADCs) in 2022 and 80 ADCs in development. [37] The importance of obtaining well defined homogeneous bioconjugates propelled the investigation of site-selective modification. The high reactivity of the thiol group is commonly exploited for the modification of cysteine residues, either by exploring the thiol nucleophilicity in the presence of electrophiles (i.e.…”

Expanding the reach of HER2-targeted therapies: transformation of an historical paradigm

“…In the last 20 years, numerous other HER2-targeted therapies have proven successful in the metastatic, adjuvant and neoadjuvant settings, including another monoclonal antibody — pertuzumab — three separate tyrosine kinase inhibitors — lapatinib, neratinib, and tucatinib — and two antibody drug conjugates (ADCs) — ado-trastuzumab emtansine (T-DM1) and fam-trastuzumab deruxtecan (TDx-D). The ADCs represent a relatively new strategy in oncology, utilizing a site-specific monoclonal antibody to direct a highly potent, conjugated cytotoxic agent directly to cancer cells overexpressing the respective antigen ( 7 ). ADCs minimize systemic drug distribution and toxicity to normal cells, permitting improved drug delivery and optimization of the therapeutic index.…”

RC48-ADC combined with tislelizumab as neoadjuvant treatment in patients with HER2 positive locally advanced muscle-invasive urothelial bladder cancer：A multi-center phase Ib/II study (HOPE-03)

“…Meanwhile, immune checkpoint inhibitors(ICIs) targeting programmed cell death protein 1 (PD-1) and programmed cell death-ligand1 (PD-L1) have signi cantly changed the treatment landscapes of locally advanced / unresectable or metastatic UC [16]. Previous studies showed the combination of RC48-ADC and PD-1 antibody may have synergistic antitumor effect, because ADC linking to MMAE elicits immunogenic cell death (ICD) and has a direct effect on DC maturation and activation, which may enhance antitumor immunity [17,18]. Moreover, combination of RC-48-ADC and PD-1 antibody con rmed an promising objective response rate (ORR) of 73.9% for metastatic UC patients without previous system treatment and a good tolerance in RC48-C014 trial [19].…”