A Novel Quaternary Ammonium-Based Drug-Linker for Antibody–Drug Conjugates
Burke et al. Page 938
Payloads for antibody–drug conjugates (ADC) remain limited in scope, as the conjugated drugs must contain certain reactive functional groups for linker attachment. Here, the development of a quaternary ammonium linker system is described to conjugate tertiary amines, a functional group present in many biologically active molecules. The linker strategy was exemplified with auristatin and tubulysin analogues containing N-terminal tertiary amines. Upon conjugation, the resulting ADCs were stable, immunologically specific, and highly active in vitro and in vivo. Thus, the quaternary ammonium linker has the hallmarks of an effective ADC linker and has expanded the repertoire of payloads that can be used.
G1T28, a Novel CDK4/6 Inhibitor, Reduces Chemotherapy-Induced Myelosuppression
Bisi et al. Page 783
Chemotherapy-induced myelosuppression leads to dose reductions and treatment delays that limit the effectiveness of chemotherapy. Here, Bisi and colleagues describe G1T28, a novel and selective CDK4/6 inhibitor, and demonstrate its ability to protect bone marrow from chemotherapy-induced damage through transiently arresting hematopoietic stem and progenitor cells in the G1 phase of the cell cycle. This novel approach is currently in Phase I/II clinical trials to reduce chemotherapy-induced myelosuppression in SCLC patients receiving either first- or second-line cytotoxic chemotherapy.
FAP-Dependent DR5 Hyperclustering Drives Tumor Cell Death
Brünker and Wartha et al. Page 946
Induction of tumor cell apoptosis by death receptor (DR)-agonistic antibodies showed only limited clinical success, most likely due to their dependence on FcγR-mediated hyperclustering. To overcome this, Brünker, Wartha, and colleagues engineered RG7386, a bispecific antibody that simultaneously binds to FAP in the tumor stroma and to DR5 on tumor cells leading to hyperclustering of DR5 and induction of apoptosis in a strictly target-dependent fashion. The authors demonstrated strong, FAP-dependent tumor cell apoptosis and superior in vivo efficacy of RG7386 over agonistic DR5 antibodies in mouse xenograft models suggesting that this approach could overcome the liabilities of conventional DR-agonistic antibodies.
dPCR and RAS Genotyping for Metastatic Colon Cancer Anti-EGFR Therapy
Azuara and Santos et al. Page 1106
The clinical significance of low-frequent RAS pathway mutated alleles and the optimal sensitivity cutoff to predict the response of anti-EGFR therapy in metastatic colon cancer patients remains controversial. Azuara, Santos, and colleagues aimed to evaluate the added value of genotyping an extended RAS panel using a nanofluidic digital PCR. An inverse correlation between the fraction of mutated alleles and radiological response was observed. A threshold of 1% optimized prediction of response, progression-free survival, and overall survival. These data indicate that mutation testing using an extended RAS gene panel with a threshold of 1% improved prediction of response to anti-EGFR therapy.