Cervical cancer is a type of cancer that develops from the cells of the cervix, the lower portion of the uterus that connects to the vagina. Cervical cancer being the fourth most common cancer in women affects more than 5,00,000 women worldwide each year and accounts for more than 3,00,000 deaths. Despite being mostly preventable, the disease continues to be the main reason for cancer-related deaths in women globally [1,2].
Understanding the current landscape of cervical cancer
Approximately 6% of women with cervical cancer are found to have primary metastatic disease, despite screening programs for early diagnosis and the availability of human papillomavirus vaccines. Furthermore, a recurrence may occur in one-third of the patients on chemoradiation, followed by brachytherapy, for advanced metastatic cancer.
The great majority of recurrent or metastatic cervical cancer with no response to locoregional therapies is ultimately regarded as an incurable disease with a very dismal prognosis. In the past, cisplatin monotherapy and later a combination of cisplatin and paclitaxel were thought to be the gold standard of treatment. Ten years ago, bevacizumab was added to chemotherapy, and the results in terms of overall survival and response rate were favorable [2,3].
Despite this development, innovative therapies are still needed for the treatment of recurrent cervical cancer in both the first and later lines. Given that immunological checkpoints play an integral role in immunosuppression, it is potentially possible to increase the anti-tumor activity of immune cells by specifically blocking immune checkpoint molecules.
Immune checkpoint inhibitors (ICIs), which are antibodies that target immune checkpoint molecules regulating the immune system's response to cancer, have been approved as first- or second-line treatments for a variety of solid tumors. ICIs, including pembrolizumab, cemiplimab, and others, have recently gained attention as innovative therapeutic pillars. These ICIs may provide persistent responses in patients and influence overall survival in the primary (in addition to chemotherapy) or recurrent (monotherapy) settings [3].
Rationale behind the use of bi-specific antibodies in the treatment of cervical cancer
Cervical cancer cells are known to evade the immune system by expressing high levels of immune checkpoint proteins. The immune checkpoint proteins in cervical cancer that have been studied the most are:
Programmed death 1/programmed death ligand-1 (PD-1/PD-L1)
Cytotoxic T lymphocyte antigen (CTLA-4).
Inhibition of these immune checkpoint proteins is being used as a monotherapy in the treatment of cervical cancer. However, in recent years, extensive research has focused on investigating how various combination therapies involving anti-PD-1 antibodies can enhance the effectiveness of PD-1 monotherapy. Recent clinical studies have demonstrated that anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) and anti-PD-1 antibody combination therapy can significantly improve efficacy for some difficult-to-treat cancer types, such as renal cell cancer, gastric cancer, and small cell lung cancer. However, the application has been constrained by severe toxicities.
As a result, innovative methods to maximize the efficacy of the use of bi-specific antibodies (PD-1 and CTLA-4 antibody combination) while minimizing toxicities represent a promising line of investigation for immune-oncology drugs [2,4].
Cadonilimab, a bi-specific IgG1 antibody
Cadonilimab (AK104) is a human tetravalent bi-specific IgG1 antibody. Cadonilimab possesses a symmetric IgG-single-chain variable fragment structure, and Fc-null design, and is used to prevent:
cytokine release.
complement-dependent cytotoxicity (CDC).
antibody-dependent cellular cytotoxicity (ADCC).
Lymphocytes that express PD-1 and CTLA-4 may be destroyed or damaged by Fc receptor-mediated effector functions, which would decrease anti-tumor effectiveness. Due to its tetravalent nature, cadonilimab has been shown to have significant binding avidity, especially to high densities of PD-1 and CTLA-4. It can also bind multiple cells that express PD-1 and CTLA-4 respectively. When compared to an anti-PD-1 and anti-CTLA-4 combination, cadonilimab can effectively activate T-cells by enhancing interleukin-2 (IL-2) and interferon-γ (IFN-γ) generation to a similar amount.
Cadonilimab showed minimal ADCC, antibody-dependent cellular phagocytosis (ADCP), CDC impact, and decreased release of pro-inflammatory cytokines including IL-6 and IL-8 with the deletion of Fc receptor binding. Lower toxicities and improved anti-tumor efficacy may be caused by these characteristics of cadonilimab [4].
Epilogue
Bi-specific antibodies are a pioneering alternative in immunotherapy and represent a revolutionary approach. These medications provide a "personalized" attack on cancerous cells, making cancer treatment more individualized and focused for cancer patients. Regarding this type of immunotherapy, there is still a lot of information that must be clarified. Future applicability will be altered by the complicated pharmacokinetics and pharmacodynamics of these medications. Finally, future research should examine potential negative consequences associated with the nature of its mode of action. Nevertheless, the evidence is encouraging and increasing, and perhaps these pharmaceuticals are the safer successors in the fight against cancer.
References
1. Cohen, P.A. et al. 'Cervical cancer'. The Lancet. (2019) 393(10167), 169–182. DOI: 10.1016/S0140-6736(18)32470-X.
2. Xie, Y. et al. 'Immune checkpoint inhibitors in cervical cancer: Current status and research progress'. Front Oncol. (2022) 12, 984896. DOI: 10.3389/fonc.2022.984896.
3. Duranti, S. et al. 'Role of Immune Checkpoint Inhibitors in Cervical Cancer: From Preclinical to Clinical Data'. Cancers (Basel). (2021) 13(9), 2089. DOI: 10.3390/cancers13092089.
4. Pang, X. et al. 'Cadonilimab, a tetravalent PD-1/CTLA-4 bispecific antibody with trans-binding and enhanced target binding avidity'. MAbs. 15(1), 2180794. DOI: 10.1080/19420862.2023.2180794.
