CD ? Did you say CD ?
In immunology, it is really useful to identify the different types of leukocytes within a sample. But distinguishing leukocytes according to their morphological or functional characteristics is not an easy job.
However, scientists discovered that leukocytes express on their surface a large number of molecules which can be used as markers for their specific identification. The concept of cell immunophenotypic identification was born.
This identification is based on the detection of these membrane markers using monoclonal antibodies followed by analysis in flow cytometry. Since 1982, these markers have been designated according to the cluster of differentiation nomenclature or CD, followed by a number. And the combination of present (CD+) and absent (CD-) markers makes possible the identification of the state of maturation of the cells.
IL2Ra/CD25/Tac : a difficult youth
Discovered in the 70's, interleukin-2 (IL-2) is a key cytokine in regulating activation and proliferation of immune T cells. The IL-2 heterotrimeric receptor (IL2R) is composed of two subunits α (p55) and β (p75). The p75 β chain, which transmits the message brought by IL-2 to the cell, is present on many cells, including resting T cells, but appears to have increased expression during alloreactions. The p55 chain appears during activation. Some monoclonal antibodies can prevent the attachment of IL-2 on this receptor and stop the activation of T cells (LO-TACT).
The assembly of IL-2 receptor is first initiated by the recognition of interleukin-2 high-affinity receptor alpha chain (IL-2Rα), followed by the recruitment of IL-2Rβ (CD122) and IL-2Rγ (CD132).
Interleukin-2 high-affinity receptor alpha chain (CD25), has been observed on activated B, T lymphocytes and macrophages. Alternative names for the antigen are often used : IDDM10, TCGFR, p55 or Tac.
Inhibiting the binding of IL-2 to CD25, anti-CD25 monoclonal antibodies have been first developed as therapeutic agents to treat organ transplant rejection and GVHD (Basilixumab, a Novartis chimeric mouse-human CD25 antibody, 1998 approval) and multiple sclerosis (Daclizumab, a Biogen humanized CD25 antibody, 1997 approval then withdraw due to safety issues).
But since CD25 is constitutively and highly expressed on regulatory T cells (Treg) cells, this marker was rapidly investigated as a potential target for inflammatory and auto-immune diseases by hitting immune system suppression.
In cancer immunotherapy field, tumors containing a higher ratio of CD4+CD25+FOXP3+ Tregs to CD8+ are supposed to be predictors of a poor prognosis for the patient.
In 2013, ADC Therapeutics and Genmab decided to partner on the development of a new antibody format as an Antibody Drug Conjugate (ADC). They combined Genmab's CD25-targeting HuMax®-TAC antibody and pyrrolobenzodiazepine (PBD) warhead technology from ADC Therapeutics. Camidanlumab (ADCT-301) was in the pipeline.
But tackling cancer with a Treg cells depletion tactic - like companies such as Hifibio Therapeutics promotes since the beginning - was quite a contested therapy approach. Since CD25 is also express by Teff, the risk of Treg immunosuppressive strategy is to kill valuable fighters of the immune system.
And until 2018, preclinical data and clinical trials have proven wrong these strategies.
CD25 : an oncology boat with the wind in its sails
Anne Goubier and her team at Tusk Therapeutics decided to develop a new version of anti-CD25 antibody that does not block the IL2 signaling (pSTAT5 mediated pathway) in order to deplete Treg and stimulate Teff at the same time. These promising antibody is going to be tested in cancer. But not by Tusk itself. At the end of 2018, Roche has paid $81 million upfront with another $677 million milestone payment to buy Tusk Therapeutics and so get complete control on this promising anti-CD25 antibody also with its anti-CD38 alter ego (1).
And since then, things seem to be accelerating again for CD25.
In 2019, NIH conjugated a near infrared silica-phthalocyanine dye to a monoclonal antibody. This process led to a new cell-specific cancer therapy that locally kills specific cells in the tumor. In this particular context, comparing full length anti-CD25 antibody with its fragment version, it appears that the absence of the Fc portion leads to faster clearance and therefore promotes a superior activated T cell response in tumors.
January 2020, Alderaan Biotechnology - a French preclinical company focused on the development of anti-CD25 monoclonal antibodies for the treatment of cancer - announced that it raised €18.5 million in a Series A financing.
October 2020, ADC Therapeutics and Genmab decided to pursue the development of Camidanlumab following the great outcomes of clinical trials (2).
September 2021, iBio made an upfront $5 million with and additional $2.5 million milestone in the context of a worldwide exclusive licensing agreement of RubrYc's RTX-003 anti-CD25 immunotherapy candidate. Under the terms, RubrYc accepts that iBio receives 17.6% equity stake in RubrYc (3).
SYnAbs therapeutic LO-TACT-1 anti-CD25
Starting in 1981, anti-CD3 OKT3 effectiveness in the treatment of organ rejection has been demonstrated by numerous studies. OKT3 mAb recognizes the CD3 antigen, which is part of the molecular assembly that makes up the antigenic receptor of all circulating T cells, and unfortunately, activates these cells by causing them to produce TNF, gamma interferon and IL-2. These cytokines cause clinical syndromes such as high fever, vomiting, diarrhea and even severe respiratory disorders that can lead to fatal outcomes. In addition, because OKT3 has a very broad spectrum of action, its use infections and a significant increase in the incidence of B lymphoma after a more or less long latency period (COSIMI et al., 1987; MILLIS et al., 1989).
SYnAbs founders so decided to develop a new therapeutic approach free of harmful side effects for the patient. After a first success in 1990 (4), Baudreuil et al decided to launch a randomized long-term study to test the LO-TACT-1 rat-LOU monoclonal anti-interleukin 2 receptor (IL2Ra/CD25) monoclonal antibody generated by SYnAbs, in the context of acute and chronic allograft rejection, also with infectious diseases following kidney transplantation (5).
During ten years, LO-TACT-1 (10mgr/day iv) demonstrated fewer bacterial and viral infections, and less cases of rejection, compared to anti-thymocyte globulin (Thymoglobuline MERIEUX, 15mg/day) treatment in forty grafted patients. Long-term graft survival was the first endpoint, and the number of cases of acute cellular and chronic rejection and the frequency of infectious event were the secondary end-points.
So far, LO-TACT-1 has never been tested in oncology and could show interesting results.
But given the saturation of the CD25 receptor and the complexity of its expression on both immune and tumor cells, it is unlikely that the future of CD25 will lead us to monotherapy approaches. Instead, we should witness the rise of many combination (with immune checkpoint inhibitors) or immuno-conjugate (with antibody-drug conjugates) therapeutic approaches to provide more effective and durable anti-tumor responses to patients.
(1) Solomon, I., Amann, M., Goubier, A. et al. CD25-Treg-depleting antibodies preserving IL-2 signaling on effector T cells enhance effector activation and antitumor immunity. Nat Cancer 1, 1153–1166 (2020). https://doi.org/10.1038/s43018-020-00133-0
(4) Hiesse C, Kriaa F, Alard P, et al. Prophylactic use of the IL-2 receptor specific monoclonal antibody LO-Tact-1 with cyclosporin A and steroids in renal transplantation. Transpl Int 1992; 5 (Suppl. 1): S444
(5) Beaudreuil S et al. (2006) Long-term results (10 years) of a prospective trial comparing Lo-tact-1 monoclonal antibody and anti-thymocyte globulin induction therapy in kidney transplantation. Transpl Int 19: 814–820