Human CD27 Antibody - Varlilumab Biosimilar

The Cluster of Differentiation CD27, a member of the TNFR family, is known as the sole receptor for CD70 (aka CD27L). 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]. In humans, CD27 is constitutively expressed on the majority of T cells, memory B cells and plasma cells, and natural killer (NK) cells. It is also expressed on various types of hematologic cancers. In leukemia, CD27 signaling leads to the induction of different pathways, supporting stemness, tumor cell proliferation, and self-renewal [3].

The efficacy of targeting the CD27/CD70 axis with an agonistic CD27 mAbs was shown in preclinical models of lymphoma, renal cell carcinoma (RCC), breast cancer, and sarcoma [4]. A human mAb directed at CD27 named varlilumab (also CDX-1127, 1F5) has entered clinical trials. It is able to activate CD27-positive T cells, while mediating the killing of CD27-expressing tumor cells [4-5]. Also, it has successfully completed a phase I/II dose escalation and cohort expansion study (NCT02335918) in combination with nivolumab in different solid malignancies. Further phase I trials with various combinations as well as phase II trials are still ongoing in renal cell carcinoma, squamous cell carcinoma of the head and neck, ovarian and colorectal cancers, and glioblastoma [4]. 

In conclusion, the CD27/70 axis is a promising pathway for immunotherapies showing a potential clinical benefit in different hematological and solid tumors. The combination of agonistic costimulatory CD27 mAbs with currently used immune checkpoint inhibitor-targeting mAbs (e.g. anti-PD-1) is foreseen to have a synergistic effect by different favorable effects on the tumor microenvironment. 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 [4]. 

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. 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. 
4. Starzer AM, Berghoff AS., 2020. New emerging targets in cancer immunotherapy: CD27 (TNFRSF7). ESMO Open. 4 (Suppl 3):e000629.
5. Vitale LA, et al.,2012. Development of a human monoclonal antibody for potential therapy of CD27-expressing lymphoma and leukemia. Clin Cancer Res. 2012 Jul 15;18(14):3812-21.