Targeting Vesicular LGALS3BP by an Antibody-Drug Conjugate as Novel Therapeutic Strategy for Neuroblastoma

Abstract

Neuroblastoma is the most common extra-cranial solid tumor in infants and children, which accounts for approximately 15% of all cancer-related deaths in the pediatric population. New therapeutic modalities are urgently needed. Antibody-Drug Conjugates (ADC)s-based therapy has been proposed as potential strategy to treat this pediatric malignancy. LGALS3BP is a highly glycosylated protein involved in tumor growth and progression. Studies have shown that LGALS3BP is enriched in extracellular vesicles (EV)s derived by most neuroblastoma cells, where it plays a critical role in preparing a favorable tumor microenvironment (TME) through direct cross talk between cancer and stroma cells. Here, we describe the development of a non-internalizing LGALS3BP ADC, named 1959-sss/DM3, which selectively targets LGALS3BP expressing neuroblastoma. 1959-sss/DM3 mediated potent therapeutic activity in different types of neuroblastoma models. Notably, we found that treatments were well tolerated at efficacious doses that were fully curative. These results offer preclinical proof-of-concept for an ADC targeting exosomal LGALS3BP approach for neuroblastomas.

Role of galectin 3 binding protein in cancer progression: a potential novel therapeutic target

“…Indeed, while initial trials of ADC focused on tumor associated antigens or tumor growth factor receptors expressed on the surface of tumor cells, more recently stromal components of the tumour microenvironment have been explored as potentially actionable targets. In this context, we have recently focused our attention to the development of a new type of non-internalizing ADC [ 101 , 102 ]. We hypothesize that this ADC might work by recognizing the antigen expressed both on the EVs surface and in the extracellular matrix, releasing the drug in the reducing space of tumor micro-environment, resulting in a potent therapeutic effect as described below.…”

“…More recently, in light of new findings on the abundance of LGALS3BP in extracellular vesicles in several cancers, we investigated the therapeutic potential of 1959-sss/DM3 in multiple pre-clinical models of human neuroblastoma expressing vesicular LGALS3BP [ 102 ]. This work proved that ADC-therapy targeting LGALS3BP in neuroblastoma induced significant shrinkage of established subcutaneous and orthotopic neuroblastomas, as well as inhibition of metastatic dissemination and complete eradication of subcutaneous high-risk neuroblastoma patient-derived xenografts (PDX)s harboring MYCN amplification.…”

Antibody–Drug Conjugate Efficacy in Neuroblastoma: Role of Payload, Resistance Mechanisms, Target Density, and Antibody Internalization

“…Furthermore, ADCs are often endowed with diverse mechanisms of tumor killing, which is particularly ideal for the often heterogeneous antigen expressing, immunosuppressive microenvironment state of solid tumors. However, due to lack of prior systematic investigation of different ADC payload classes in neuroblastoma, drug selection for neuroblastoma targeting ADCs to date has been achieved by arbitrary selection of payloads based on efficacy in other cancer histotypes (7)(8)(9)34). Thus, our first aim here was to assess the potency of membrane permeable ADC payloads in a diverse panel of neuroblastoma cellular models to define which payloads would be most optimal to utilize in ADCs targeting this pediatric cancer.…”

Novel Treatments and Technologies Applied to the Cure of Neuroblastoma

“…The 1959-sss/DM3 molecule was made by combining an engineered humanised anti-LGALS3BP Ab with DM3, a chemical derivative of maytansine with a cell-killing potency in the picomolar range. Interestingly, preclinical mouse models showed high efficacy in eradicating both orthotopic and metastatic NBs [11] (Table 1).…”