Naxitamab: a humanized anti-glycolipid disialoganglioside (anti-GD2) monoclonal antibody for treatment of neuroblastoma.

Therapy for high-risk neuroblastoma (HR NBL) is comprised of multimodal therapy including chemotherapy, surgery, radiation therapy, myeloablative therapy followed by autologous hematopoietic stem cell transplant, and immunotherapy. GD2 is a disialoganglioside that is highly expressed on the surface of neuroblastoma cells, with limited expression on normal tissues, which makes it an attractive target for immunologic therapy. The combination of immunotherapy with murine and chimeric anti-GD2 antibody formulations has improved outcomes compared with standard therapy in HR NBL patients. Naxitamab (Danyelza), a fully humanized anti-GD2 antibody, was developed at Memorial Sloan Kettering Cancer Center (MSKCC) to mitigate adverse reactions related to intolerance of foreign murine and chimeric antigens. Phase I and II studies demonstrating the tolerability and efficacy of naxitamab in patients with relapsed/refractory (r/r) HR NBL prompted its approval by the U.S. Food and Drug Administration (FDA) in 2020 for HR NBL with bone or bone marrow involvement. Initial outcomes with naxitamab are encouraging; however, future trials to maximize drug tolerance and elucidate its optimal role in neuroblastoma therapy in conjunction with other treatment strategies are needed. This review discusses the use of naxitamab in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment of r/r HR NBL.

CFEOM3: a new extraocular congenital fibrosis syndrome that maps to 16q24.2-q24.3.

PURPOSE: To define the clinical characteristics and determine the gene localization for a previously undescribed form of congenital fibrosis of the extraocular muscles (CFEOM), referred to as CFEOM type 3 (CFEOM3). METHODS: A large family with CFEOM was identified, and participating individuals underwent ophthalmologic examination and donated blood for genetic analysis. The family's disorder was tested for linkage to the known CFEOM loci, followed by a genome-wide search and linkage refinement using polymorphic DNA markers. RESULTS: Thirty-eight members of this Canadian family participated in the study. Affected individuals are born with a nonprogressive eye movement disorder characterized by variable expression of ptosis and restrictive external ophthalmoplegia. Severely affected individuals have ptosis, primary gaze fixed in a hypo- and exotropic position, and marked restriction of eye movement bilaterally. Mildly affected individuals have normally positioned globes with a limitation of vertical gaze. Moderately affected individuals have asymmetrical involvement with one eye severely and one eye mildly affected. The disorder is autosomal dominant with variable expression and probable incomplete penetrance. Genetic analysis reveals linkage to markers on 16q24.2q24.3. A maximum lod score of 5.8 occurs at markers D16S3063 and D16S689, and the CFEOM3 disease gene is located within a 5.6-cM region flanked by D16S486 and D16S671. CONCLUSIONS: These data establish that CFEOM3 is a phenotypically variant and genotypically distinct form of CFEOM with linkage to chromosome 16qter. The authors have previously demonstrated that CFEOM1 results from a developmental absence of the superior division of the oculomotor nerve. The authors hypothesize that CFEOM3 results from a defect analogous to, but distinct from CFEOM1.

A gene for isolated congenital ptosis maps to a 3-cM region within 1p32-p34.1.

Hereditary isolated congenital ptosis is an autosomal dominant disorder with incomplete penetrance characterized by a variable degree of unilateral or bilateral drooping of the upper eyelids. We report linkage of this disorder in a large family to markers on chromosome 1p. In our sample of 37 meioses, nine informative markers did not recombine with the disease. D1S2677 gave a maximum two-point LOD score of 8.8 on the assumption of 90% penetrance (theta = 0). D1S447/2733 and D1S1616 flank the disease locus, with two-point LOD scores of 5.6/6.6 (theta = .04) and 4.9 (theta = .05), respectively, defining a region of 2.8 cM. FISH of YACs containing flanking recombinant markers localizes the gene to chromosome 1p32-p34.1. These data establish a map location for an isolated congenital ptosis gene and demonstrate that this disorder is genetically distinct from other extraocular muscle-specific disorders such as congenital fibrosis of the extraocular muscles and blepharophimosis.