Human CTLA4 (CD152) Antibody - Ipilimumab IgG1fut Isotype

The cytotoxic T-lymphocyte-associated protein 4 (CTLA-4, CD152) is an inhibitory receptor and immune checkpoint expressed by activated and regulatory T cells [1, 2].

The current paradigm is that full activation of T cells requires at least 2 signals upon contact with antigen-presenting cells (APCs) [3, 4]. Signal 1 is delivered upon the interaction of the T cell receptor (TCR) with antigenic peptides bound to major histocompatibility complex (MHC) molecules on antigen-presenting cells (APCs). Signal 2 is delivered upon the interaction of the co-stimulatory receptor CD28 with the B7 family ligands, B7-1 (CD80) and B7-2 (CD86), on APCs.

Signal 1: TCR and [HLA::peptide]

The 'classical' and most represented TCR is an 80 to 90 kDa heterodimer composed of one α chain and one β chain. The αβTCR is a transmembrane protein expressed by developing and mature T cells. It features an extracellular ligand-binding pocket and a short cytoplasmic tail. Each αβTCR is restricted to a specific complex made of an antigenic peptide and a class I or class II MHC molecule. Human MHC molecules are also known as HLA (human leukocyte antigen). Because of its short cytoplasmic tail, the TCR, once engaged, cannot signal and requires non-covalent association with the CD3 to trigger downstream intracellular signaling and T cell activation [3, 4]. Importantly, signal 1 without co-stimulation results in T cell unresponsiveness or 'anergy', a tolerance mechanism that guards against premature activation.

Signal 2: CD28 and CD80/86

CD28 is a homodimeric and transmembrane protein expressed by T cells. Nearly all human CD4+ T cells and 50% of human CD8+ T cells express CD28. The CD28 interaction with CD80 (aka B7-1) or CD86 (aka B7-2) on APCs, in conjunction with TCR engagement, triggers a co-stimulation signal (signal 2). It results in T-cell proliferation, cytokine production, cell survival, and cellular metabolism [3, 4].

IC signal: CTLA-4 and CD80/86

CTLA-4 exerts competitive binding to the co-stimulatory receptor CD28 ligands (i.e. CD80 and CD86) expressed by antigen-presenting cells. Thereby CTLA-4 upregulation by T cells prevents overstimulation.
Anti-CTLA-4 monoclonal antibodies (mAbs), as well as other immune checkpoints targeting mAbs, are extensively investigated to treat various cancers [2, 5, 6].

Ipilimumab background

Ipilimumab, a fully human IgG1 monoclonal antibody targets the Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4), also known as CTLA4 or CD152. CTLA-4 is an important immune checkpoint and negative regulator of T cell activation. Upon binding to CTLA-4, Ipilimumab inhibits negative signals that physiologically downregulate T cell activation and exerts its therapeutic activity by upregulating the antitumor activity of T lymphocytes [7,8]. In addition, Ipilimumab induces antibody-dependent cell-mediated cytotoxicity (ADCC) and TNF-α production [9]. Ipilimumab is FDA-approved for the treatment of unresectable or metastatic melanoma and is undergoing various clinical trials for other types of cancers, including lung cancer [10].

References:

1. Ribas A. and Wolchock J.D. 2018. Cancer immunotherapy using checkpoint blockade. Science. 359:1350.
2. Wei, S.C. et al. 2018. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 8(9):1069.
3. Budd R.C. & Fortner K.A., 2017. Chapter 12 - T Lymphocytes. Kelley and Firestein's Textbook of Rheumatology (Tenth Edition). pages 189-206.
4. Smith-Garvin J.E. et al., 2009. T Cell Activation. Ann. Rev. Immunol. 27:591-619.
5. Wilson, R.A.M. et al. 2018. Immune checkpoint inhibitors: new strategies to checkmate cancer. Clin. Exp. Immunol. 191(2):133-148.
6. Marin-Acevedo J.A. et al. 2018. Next generation of immune checkpoint therapy in cancer: new developments and challenges. J. Hematol. Oncol. 11(1):39.
7. Grosso JF. & Jure-Kunkel MN., 2013. CTLA-4 blockade in tumor models: an overview of preclinical and translational research. Cancer Immun. 13:5.
8. Maio M. et al., 2013. Update on the role of ipilimumab in melanoma and first data on new combination therapies. Curr Opin Oncol. 25:166-72.
9. Laurent S.. et al., 2013. The engagement of CTLA-4 on primary melanoma cell lines induces antibody-dependent cellular cytotoxicity and TNF-α production. J Transl Med. 11:108.
10. Tomasini P., 2012. Ipilimumab: its potential in non-small cell lung cancer. Ther Adv Med Oncol. 4: 43–50.