NextCure : NC605 ASBMR Poster 2023

Sexual Dimorphism in Treatment Effect of Anti-Siglec 15 in Adult Mice with Moderate-to-Severe Osteogenesis Imperfecta

Ketsia Seide1; Jack Mulcrone1; Erin Carter1; Priyanka Kothari3; Sol Langermann3; Shanmugam Selvam3; Nancy Pleshko2; Cathleen Raggio1

1Hospital For Special Surgery, 2Temple University, 3NextCure, Inc.

Introduction

• Osteogenesis imperfecta (OI) is a heterogeneous type 1 collagenopathy that alters either the quantity or quality of type I collagen. It is characterized by bone fragility which often leads to high fracture incidence.
• Bisphosphonates are commonly used to treat children with moderate-to-severe forms of OI, but gaps persist for effective pharmacological treatment in adult patients.
• The oim/oim mouse is an established model of moderate-to- severe OI that contains a naturally-occurringcol1a2 variant that leads to proα2(I) collagen deficiency [1].
• We previously demonstrated that a monoclonal antibody targeting the sialic acid-bindingimmunoglobulin-like lectin 15 (Siglec 15) immunoreceptor [2], NP159 (NextCure), improves bone quality and decrease fractures in female oim mice.
• We have now extended the study to evaluate efficacy in male oim mice.

Results

• 90% of male oim/oim treated with NP159 had no new fractures, versus 85% of females seen earlier (Figure 1).
• Micro-CT(Figures 2, 3, and 4):
• • Both sexes showed decreased trabecular separation with NP159 treatment (p=0.05).
  • Treated males had normal cortical porosity, in contrast with females who showed increased porosity.
  • Bone mineral density did not change for either sex.
• Biomechanics (Figure 5): NP159 increased stiffness of the bones in both males and females.
• FTIR:
• • females showed a normalization of mineral:matrix ratio, increased acid phosphate, and decreased collagen maturity, whereas the males showed no similar changes.

Figure 2. Male Micro-CT results

Figure 4. Female Micro-CT results

Figure 5. Male + Female Stiffness results

Figure 3. Micro-CT 3D images of oim/oim trabecular bone

Females

Males

Methods and Materials

• Eighty male mice (20 wildtype (WT) saline, 20 WT NP159, 20 oim/oim saline, and 20 oim/oim NP159) were treated from age 14-26 weeks with either NP159 (10mg/kg weekly x1 month then biweekly) or weekly saline.
• Faxitrons at 14 and 26 weeks were taken to evaluate fracture incidence and healing.
• Tibias and femurs were analyzed post-sacrifice for femoral length, microcomputed tomography (micro-CT), biomechanical testing, and Fourier Transform Infrared Spectroscopy (FTIR).
• Statistical analysis was performed using Two-way analysis of variance (ANOVA). A p≤0.05 was considered significant.
• Results were compared to the previous study using female mice.

Figure 1. Male + Female Fracture Count results

14 weeks		26 weeks

Number of Fractures

Conclusions

•	These results show promising trends for NP159 treatment in OI.
•	Fracture incidence was reduced.
•	The observed cortical and trabecular bone changes support the
	premise that NP159 works as both an antiresorptive and a bone
	formation agent.
•	NP159 seems to be favorable for bone strength in both sexes as
	indicated by the increased stiffness shown on biomechanical
	testing.

Contact

Dr. Cathleen Raggio, MD

Hospital for Special Surgery | New York, NY Email: [e-mail]

Phone: [phone]

Disclosure

This study was funded by NextCure

References 1.Chipman SD, Sweet HO, McBride DJ Jr, Davisson MT, Marks SC Jr, Shuldiner AR, Wenstrup RJ, Rowe DW, Shapiro JR. Defective pro alpha 2(I) collagen synthesis in a recessive mutation in mice: a model of human osteogenesis imperfecta. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1701-5.

2.Sato D, Takahata M, Ota M, Fukuda C, Tsuda E, Shimizu T, Okada A, Hiruma Y, Hamano H, Hiratsuka S, Fujita R, Amizuka N, Hasegawa T, Iwasaki N. Siglec-15-targeting therapy increases bone mass in rats without impairing skeletal growth. Bone. 2018 Nov;116:172-180.

•	Sexual dimorphism is a known phenomenon in both human
	patients and previously reported treated mice models.
•	The sex-specific results seen with NP159 treatment highlights
	the importance of considering sex when searching for possible
	therapies for OI.