New Rabbit mAbs for B7-H3 and B7-H4

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The healthy immune system employs a series of checkpoints in order to maintain self-tolerance or prevent collateral tissue damage during an immune response. Activation of T lymphocytes by antigen-presenting cells (APCs) requires engagement of the T cell receptor with MHC class I or II molecules and co-stimulatory signals generated from CD28 (on T cells) binding to CD80 or CD86 (on APCs). However, under certain circumstances, T cell engagement is coupled with inhibitory signals that repress T cell activation and response, known as immune checkpoints.

Immune checkpoint proteins such as PD-1 and CTLA-4, which are commonly upregulated in infiltrating T cells, bind their corresponding ligands, PD-L1 and CD80/86 respectively, and downregulate the T cell response. Immune checkpoint ligands are often upregulated in cancer cells as a means to evade immune detection (1,2). Activating antitumor immunity through the blockade of immune checkpoint proteins has become a promising therapeutic strategy for the treatment of cancer (3,4).

Below is a table of stimulatory and inhibitory receptor-ligand complexes, which mediate activation or dampening of the T-cell response, respectively.

Cellular Response T cell Antigen presenting cell
Co-stimulatory CD28 B7-1 (CD80) or B7-2 (CD86)
CD40L CD40
TLT-2? B7-H3
OX40 (CD134) OX40L
4-1BB (CD137) 4-1BBL
ICOS ICOSL
GITR GITRL
Co-inhibitory CTLA-4 B7-1 (CD80) or B7-2 (CD86)
PD-1 B7-H1 (PD-L1) or B7-DC (PD-L2)
Unknown B7-H3
Unknown B7-H4
Unknown VISTA
VISTA Unknown
LAG-3 MHC-Class II
TIM-3 Galectin-9

References:

  1. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12(4), 252–64.
  2. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8(8), 793–800.
  3. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366(26), 2455–65.
  4. Brahmer JR, Pardoll DM (2013) Immune checkpoint inhibitors: making immunotherapy a reality for the treatment of lung cancer. Cancer Immunol Res 1(2), 85–91.