Antibody drug conjugate development in gastrointestinal cancers: hopes and hurdles from clinical trials

Abstract

Gastrointestinal (GI) cancers represent the leading cause of cancer-related mortality worldwide. Antibody drug conjugates (ADCs) are a rapidly growing new class of anti-cancer agents which may improve GI cancer patient survival. ADCs combine tumour-antigen specific antibodies with cytotoxic drugs to deliver tumour cell specific chemotherapy. Currently, only two ADCs [brentuximab vedotin and trastuzumab emtansine (T-DM1)] have been Food and Drug Administration approved for the treatment of lymphoma and metastatic breast cancer, respectively. Clinical research evaluating ADCs in GI cancers has shown limited success. In this review, we will retrace the relevant clinical trials investigating ADCs in GI cancers, especially ADCs targeting human epidermal growth receptor 2, mesothelin, guanylyl cyclase C, carcinogenic antigen-related cell adhesion molecule 5 (also known as CEACAM5) and other GI malignancy specific targets. We will review potential hurdles for their success and provide new perspective for future treatment.

Phase I study of the recombinant humanized anti-HER2 monoclonal antibody–MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors

“…The safety profile of RC48 was consistent with what would be expected of a HER2-targeted antibody–drug conjugate that uses monomethyl auristatin E as its payload [ 10 ]. The most common classes of treatment-related adverse events were gastrointestinal disorders, hematological toxicities, and nerve toxicities.…”

“…Therefore, unlike T-DM1 with minimal bystander effect on nearby cells due to poor membrane permeability, RC48 has a bystander effect which can reverse T-DM1 resistance by acting on populations of cells not overexpressing HER2 [ 16 , 21 ]. Despite the failure of T-DM1 in gastric cancer, several other antibody–drug conjugates are under investigation, varying in antibody and linker payload [ 10 , 22 , 23 ]. There are currently six HER2 directed ADCs in varying stages of clinical development in patients with HER2 overexpressing gastrointestinal malignancies [ 12 ].…”

“…Currently, novel agents and combinations are being actively investigated in HER2-positive gastric cancers. Antibody–drug conjugates (ADC), comprised of an antibody against the antigen of interest, a linker, and a payload cytotoxic agent, are designed for specific delivery of cytotoxic agents to malignant cells [ 10 – 12 ]. RC48 contains the novel humanized anti-HER2 antibody hertuzumab conjugated to monomethyl auristatin E (MMAE) via a cleavable linker.…”

Advancements in Antibody–Drug Conjugate Technology for Cancer Treatment

“…They are also less effective substrates of drug resistance transporters [7]. Although tubulin inhibitors showed robust activity through a substantial number of clinical trials, a modest response rate was observed in the colon and gastric tumors [8].…”