• NTRK1 is a membrane-bound receptor that upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. The presence of this kinase leads to cell differentiation and may play a role in specifying sensory neuron subtypes.
• NTRK gene fusions are the best-characterized aberrations among all NTRK alterations occurring in cancers. These gene fusions are known to be oncogenic, as they promote tumorigenesis through the constitutive activation of downstream cell growth and proliferative pathways.
• Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand.
• NGF has nerve growth stimulating activity and the complex is involved in the regulation of growth and the differentiation of sympathetic and certain sensory neurons.

Strain specific analysis of NTRK1 and NGF mRNA expression in wild-type C57BL/6 mice and B-hNTRK1/hNGF mice by RT-PCR. Brain RNA were isolated fromwild-type C57BL/6 mice (+/+) and homozygous B-hNTRK1/hNGF mice (H/H; H/H), then cDNA libraries were synthesized by reverse transcription, followed by PCRwith mouse or human NTRK1 (A) and NGF (B) primers. Mouse Ntrk1 and Ngf mRNA were detectable only in wild-type C57BL/6 mice.

Western blot analysis of NTRK1 protein expression in homozygous B-hNTRK1/hNGF mice. Various tissue lysates were collected from wild-type C57BL/6 mice (+/+) and homozygous B-hNTRK1/hNGF mice (H/H), and then analyzed by western blot anti-m/hNTRK1 antibody. 80 μg total proteins were loaded for western blotting analysis.

NGF expression analysis in homozygous B-hNTRK1/hNGF mice by ELISA. Plasma were isolated from wild-type C57BL/6 mice (+/+) and homozygous B-hNTRK1/hNGF mice (H/H) (n=3, female, 6-week-old), and analyzed by ELISA with NGF ELISA kit.

Experimental schedule for the in vivo efficacy of Tanezumab in B-hNTRK1/hNGF mice. Mice were acclimated from day 1 to 3. CFA was administered on day 4 to induce inflammatory pain. The baseline von Frey test for grouping was performed 2 hours prior to drug administration on day 5. Tanezumab was administered by intraperitoneal (i.p.) injection on day 5. Subsequent von Frey tests were performed on days 6, 7, 8, 11, and 14 to evaluate mechanical allodynia. CFA, Complete Freund's Adjuvant.

Tanezumab increased paw withdrawal thresholds in both wild-type and B-hNTRK1/hNGF mice compared with vehicle controls. (A) Baseline paw withdraw thresholds confirmed comparable initial values between Wild-type (WT) and B-hNTRK1/hNGF mice. (B) Following CFA administration, Tanezumab analog treatment significantly increased thresholds in both WT and B-hNTRK1/hNGF mice compared to the vehicle-treated group, with therapeutic efficacy observed from day 6 through 11, peaking at day 8.