Data from The B7-H3–Targeting Antibody–Drug Conjugate m276-SL-PBD Is Potently Effective Against Pediatric Cancer Preclinical Solid Tumor Models

Abstract

<div>AbstractPurpose:<p>Patients with relapsed pediatric solid malignancies have few therapeutic options, and many of these patients die of their disease. B7-H3 is an immune checkpoint protein encoded by the <i>CD276</i> gene that is overexpressed in many pediatric cancers. Here, we investigate the activity of the B7-H3–targeting antibody–drug conjugate (ADC) m276-SL-PBD in pediatric solid malignancy patient-derived (PDX) and cell line–derived xenograft (CDX) models.</p>Experimental Design:<p>B7-H3 expression was quantified by RNA sequencing and by IHC on pediatric PDX microarrays. We tested the safety and efficacy of m276-SL-PBD in two stages. Randomized trials of m276-SL-PBD of 0.5 mg/kg on days 1, 8, and 15 compared with vehicle were performed in PDX or CDX models of Ewing sarcoma (<i>N</i> = 3), rhabdomyosarcoma (<i>N</i> = 4), Wilms tumors (<i>N</i> = 2), osteosarcoma (<i>N</i> = 5), and neuroblastoma (<i>N</i> = 12). We then performed a single mouse trial in 47 PDX or CDX models using a single 0.5 m/kg dose of m276-SL-PBD.</p>Results:<p>The vast majority of PDX and CDX samples studied showed intense membranous B7-H3 expression (median H-score 177, SD 52). In the randomized trials, m276-SL-PBD showed a 92.3% response rate, with 61.5% of models showing a maintained complete response (MCR). These data were confirmed in the single mouse trial with an overall response rate of 91.5% and MCR rate of 64.4%. Treatment-related mortality rate was 5.5% with late weight loss observed in a subset of models dosed once a week for 3 weeks.</p>Conclusions:<p>m276-SL-PBD has significant antitumor activity across a broad panel of pediatric solid tumor PDX models.</p></div>

Lineage-dependence of the neuroblastoma surfaceome defines tumor cell state-dependent and independent immunotherapeutic targets

“…In our recent preclinical study using a CD276-targeted ADC (m276-SL-PBD), we observed an objective response rate of 93% in the neuroblastoma cell line-derived and patient-derived xenografts. 19 Importantly, all neuroblastoma PDXs assessed display a strong ADRN signature, so the efficacy of CD276-targeted agents, as well as other preclinical molecules, remains to be determined in MES-dominant neuroblastomas. While antigen loss is a known mechanisms of escape from many immunotherapies, our data suggest that this might largely occur by epigenetic mediated cell state transitions in neuroblastoma and this needs to be considered in ongoing and future clinical trials.…”

“…For murine efficacy studies, we engrafted CB17 severe combined immunodeficiency (SCID) mice with cell line-derived xenografts (CDXs) or patient-derived xenografts (PDXs) and followed the standard protocol established in the Pediatric Preclinical Testing Consortium (now named Pediatric Preclinical In Vivo Testing, PIVOT). 19 In brief, mice with tumors at enrollment size (0.2-0.3 cm 3 ) received 1 mg/kg of either ADCT-601 or B12-PL1601 via tail vein injection. Studies were performed with N=6 animals per arm and the mice were monitored for 100 days or until their tumor burden reached 2.0 cm 3 .…”

“…Monoclonal antibodies, ADCs, and CARs specific to B7-H3 are being explored in preclinical and clinical studies. [18][19][20][21] GPC2 is a glypican protein anchored to the cell surface that was discovered as an oncogene in neuroblastoma and has been targeted with ADC and a CAR T cell approaches [22][23][24][25] , including an ongoing clinical trial (NCT05650749). It is also important to understand how heterogeneity and plasticity affect expression of immunotherapeutic targets such that we can prioritize the many therapeutic strategies in development and to uncover novel targets enriched in therapy-resistant cells.…”

A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma

“…Several other surface proteins have been nominated as candidate immunotherapeutic targets in neuroblastoma, including L1CAM [17], ALK [7,[18][19][20], GPC2 [21], DLL3 [22] and B7H3 [23,24]; however, no non-GD2 directed immunotherapy has to date shown significant anti-tumor activity in patients [25] .…”

“…were grown in CB17SC scid -/-female (5-8 weeks) mice following protocols established by the Institutional Animal Care and Use Committee (IACUC) at the Children's Hospital of Philadelphia. Tumors were then removed from mice, dissected into 250 mg sections, washed with PBS, snap frozen in liquid nitrogen, and stored at -80 freezer [23]…”