Human CD70 Antibody - Vorsetuzumab IgG1fut Isotype

The Cluster of Differentiation CD70 (aka CD27L, TNFSF7), a member of the TNFR family, is known as the sole ligand for CD27. The CD27–CD70 costimulatory receptor-ligand pair plays an important role in immune regulation. In concert with the T cell receptor (TCR) crosslinking, it promotes T cell activation, proliferation, survival, maturation of effector capacity, and T cell memory [1-2]. CD70 is primarily expressed on antigen-presenting cells (APCs) and upon interaction,with T cell-expressed CD27, it initiates the necessary signaling required for the proliferation and differentiation of antigen-specific T cells. Interestingly, it has been established that CD70 itself is transiently expressed on T cells after their activation. Evidence shows that T cell-expressed CD70 plays an important immune checkpoint role in the suppression of inflammatory T cell responses by a number of mechanisms including the upregulation of inhibitory immune checkpoint molecules [3]. Thus, the expression of CD70 on T cells has the ability to ameliorate inflammation and therefore, may be beneficial in the treatment of inflammatory diseases, such as inflammatory bowel disease (IBD) and graft-versus-host disease (GVHD) [3].

Constitutive overexpression of CD70 has been described in a range of solid and hematological malignancies, whereby tumor cells have hijacked the CD27-CD70 signaling pathway to facilitate immune evasion in the tumor microenvironment (TME) [4]. They do this by increasing the amount of suppressive regulatory T cells (Tregs), inducing caspase-dependent apoptosis of T cells, and skewing T cells towards exhaustion, to ensure they circumvent the immune response [1]. Additionally, the presence of CD70 on cancer stem cells has been shown to be a predictive marker for metastasis and poor prognosis [5]. Exploiting CD70-targeting in cancer patients has the potential to specifically eliminate the CD70-expressing cancer cell populations and abrogate the tumor-promoting mechanisms by the CD70-CD27 signaling axis, both in the early stage and advanced disease. Combinatorial approaches with anti-CD70 targeting therapies have proven their potential in both preclinical and clinical settings, using antibody-mediated therapy, chemotherapy, and Chimeric Antigen Receptor (CAR)-T cell therapy [6]. 

In conclusion, CD70 targeting agents like CD70-directed mAbs bear the potential of effectively targeting CD70-expressing solid and hematological tumors. Further clinical trials are needed to investigate potential combinations of immune-modulating therapies, especially at earlier stages of disease, to achieve the best possible outcome for cancer patients [7].

References:

1. Jacobs, J. et al. 2015. CD70: An emerging target in cancer immunotherapy. Pharmacol Ther 155, 1-10.
2. Sanborn RE, et al., 2022 Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors. J Immunother Cancer. 2022 Aug;10(8):e005147.
3. O'Neill, R.E. et al. 2017. T Cell-Derived CD70 Delivers an Immune Checkpoint Function in Inflammatory T Cell Responses. J Immunol 199, 3700-3710.
4. Jacobs, J. et al. 2018. Unveiling a CD70-positive subset of cancer-associated fibroblasts marked by pro-migratory activity and thriving regulatory T cell accumulation. Oncoimmunology 7, e1440167.
5. Liu, L. et al. 2018. Breast cancer stem cells characterized by CD70 expression preferentially metastasize to the lungs. Breast Cancer 25, 706-716.
6. Flieswasser, T., Van den Eynde, A., Van Audenaerde, J. et al. 2022. The CD70-CD27 axis in oncology: the new kids on the block. J Exp Clin Cancer Res 41, 12.
7. Starzer AM, Berghoff AS., 2020. New emerging targets in cancer immunotherapy: CD27 (TNFRSF7). ESMO Open. 4 (Suppl 3):e000629.