A novel CD7-directed antibody-drug conjugate targeting BCL-XL with potent anti-leukemic activity in T-cell acute lymphoblastic leukemia.
The paper reports that a CD7-directed antibody-drug conjugate delivering a BCL-XL-selective inhibitor kills T-ALL cell lines, shows platelet-sparing anti-leukemic activity in patient-derived xenografts, and improves mouse remission and survival when combined with venetoclax and chemotherapy.
Open original publication →What the AI sees
The paper reports that a CD7-directed antibody-drug conjugate delivering a BCL-XL-selective inhibitor kills T-ALL cell lines, shows platelet-sparing anti-leukemic activity in patient-derived xenografts, and improves mouse remission and survival when combined with venetoclax and chemotherapy.
Research significance
The supplied preclinical evidence supports targeted delivery of a BCL-XL inhibitor to CD7-positive T-ALL as a way to retain anti-leukemic activity while reducing on-target platelet toxicity; it remains an inference—not demonstrated in patients—that this strategy, alone or with venetoclax and chemotherapy, could improve treatment or serve as a bridge to HSCT.
Source abstract
Current treatments of T-cell acute lymphoblastic leukemia (T-ALL) are based on intensive chemotherapy regimens which provide overall survival rates of ~85% in children and <50% in adults. Therefore, there is an unmet need for novel therapeutic options in T-ALL. Pre-clinical studies and clinical trials have demonstrated that inhibitors of BCL-XL and/or BCL-2, two anti-apoptotic proteins of the BCL-2 family, are anti-leukemic in T-ALL. However, BCL-XL inhibitors (BCL-XLi) efficacy is undermined by severe, on-target thrombocytopenia. We report here the design of a novel anti-hCD7 mAb-based ADC carrying a BCL-XL-selective inhibitor (ADC-CD7-BCL-XLi) that circumvents this significant limitation. We show that ADC-CD7-BCL-XLi efficiently kills most T-ALL cell lines. Using T-ALL PDXs we further show that (i) ADC-CD7-BCL-XLi displays potent anti-leukemic activity and is devoid of toxicity to platelets; (ii) ADC-CD7-BCL-XLi acts synergistically with venetoclax, a BCL-2 selective antagonist, to prolong leukemia remission and mouse survival; (iii) the anti-leukemic effect of the ADC-CD7-BCL-XLi+venetoclax combination can lead to cure when combined with chemotherapy. These pre-clinical data strongly support the evaluation of ADC-CD7-BCL-XLi in T-ALL patients, including as a potential bridging option to curative hematopoietic stem cell transplantation (HSCT).