|Strain Name||C57BL/6-Ctla4tm1(CTLA4)Tnfrsf4tm1(TNFRSF4)/Bcgen||Common Name||B-hCTLA4/hOX40 mice|
Ctla4 (cytotoxic T-lymphocyte-associated protein 4)
Tnfrsf4 （Tumor necrosis factor receptor superfamily, member 4, also known as OX40）
CTLA4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152, competitively binds to B7-1 (CD80) and B7-2 (CD86) on Antigen-Presenting Cells (APCs) to block the T cell activating signal by B7 and CD28 (on T cells) interaction. The inhibition of CTLA4 by its inhibitory antibodies enhances T cell activity. The CTLA4 antibody is the first FDA-approved antibody to treat advanced melanoma. OX40, also known as Tnfrsf4 (Tumor necrosis factor receptor super family, member 4), is mainly expressed on the surface of activated CD4+ and CD8+ T cells, and its binding with the OX40 ligand can stimulate CD8+ T Cell Activation. The coactivation of OX40/OX40L enhances T cell function, including cytokine production, proliferation and T cell survival. An OX40 agonist can reduce Regulatory T cells (Tregs) and improve anti-tumor activity.
Protein expression analysis
Strain specific CTLA4 and OX40 expression analysis in homozygous B-hCTLA4/hOX40 mice by flow cytometry. Splenocytes were collected from WT and homozygous B-hCTLA4/hOX40 (H/H) mice stimulated with anti-CD3ε in vivo (7.5 μg/mice), and analyzed by flow cytometry with species-specific anti-CTLA4 antibody. Mouse CTLA4 and OX40 were exclusively detected in WT mice. Human CTLA4 CTLA4 and OX40 were exclusively detected in homozygous B-hCTLA4/hOX40 but not WT mice.
Combination therapy of CTLA4 mAb (ipilimumab) and OX40 mAb
Antitumor activity of anti-hOX40 antibody combined with anti-hCTLA4 antibody ipilimumab in B-hCTLA4/hOX40 mice. (A) Anti-hOX40 antibody combined with anti-hCTLA4 antibodies ipilimumab inhibited MC38 tumor growth in B-hCTLA4/hOX40 mice. Murine colon cancer MC38 cells (5×105) were subcutaneously implanted into homozygous B-hCTLA4/hOX40 mice (female, 5-8 week-old, n=8). Mice were grouped when tumor volume reached approximately 150±50 mm3, at which time they were treated with anti-hOX40 antibody combined with anti- hCTLA4 antibody ipilimumab with doses and schedules indicated in panel (B) Body weight changes during treatment. As shown in panel A, combination of anti-hOX40 and anti-hCTLA4 antibody shows more inhibitory effects than individual groups, demonstrating that the B-hCTLA4/hOX40 mice provide a powerful preclinical model for in vivo evaluating combination therapy efficacy of hOX40 antibodies and h B-hCTLA4 antibodies. Values are expressed as mean ± SEM.