The field of oncology has witnessed remarkable advancements in the development of anti-tumor monoclonal antibodies (mAbs) which have revolutionized cancer treatment strategies. Anti-tumor therapeutic antibodies can act on tumors via several mechanisms. They can directly target tumor cells either with an antibody-drug conjugate (such as ado-trastuzumab emtansine) or by inhibiting survival signaling pathways of cancer cells (EGFR inhibitors such as cetuximab and necitumumab). Some anti-tumor antibodies instead indirectly target cancer cells by increasing anti-tumor immune responses (immune checkpoint inhibitors such as nivolumab and pembrolizumab) or by modulating the functionalities of components within the tumor microenvironment (anti-tumor angiogenesis therapy such as bevacizumab).
Antibody-based anti-cancer therapy shows promising efficacy and generally has a better safety profile than small molecule-based anti-cancer drugs. However, many cancers do not respond or develop resistance to this form of therapy. While this loss of efficacy contributes to the majority of failures during therapeutic antibody development, therapeutic antibody-induced severe life-threatening toxicities are another critical attribute for such shortcomings, especially with the dramatic increase in the use of novel regimens of therapeutic antibodies. These novel regimens include but are not limited to (1) antibodies against novel targets, (2) combination therapy, e.g., multiple therapeutic antibodies, chemotherapy, small molecule targeted therapy combinations, and (3) new forms of therapeutic antibodies developed by modifications to the antibody structure, such as changes of glycosylation that are known to affect antibody-dependent cellular cytotoxicity (ADCC). Although a better understanding of the mechanism of action of therapeutic antibodies and a better design of clinical trials hold the key to limiting unintended toxicities, safety issues can still arise from other aspects of drug development, such as manufacturing a highly complex molecule such as a bi-specific or a tri-specific antibody.
With the enormous challenges inherent in developing an effective and safe therapeutic antibody, we hope this Research Topic will raise awareness and facilitate a rigorous discussion on the significant safety issues that arise during the development of anti-tumor monoclonal antibodies. Therefore, we invite Perspective, Review, Minireview, and Original Research manuscripts describing recent discoveries or thoughts related to safety issues in developing antibody-based anti-cancer therapy. We are particularly interested in the following subjects:
- Understanding the biology, structure, and function of anti-tumor antibodies to facilitate the development of safe and effective therapies;
- Preclinical models to assess safety profiles, including advances in three-dimensional tissue-engineered cell culture models that can potentially reduce or replace the usage of animal models;
- Developing clinical monitoring strategies to identify safety issues during the early stages of clinical trials;
- Lessons learned from successful clinical trials, or trials that failed due to safety concerns;
- Identification of biomarkers to predict the potential toxicity of anti-tumor antibodies;
- Understanding critical quality attributes and their impact on overall product safety;
- Identification of potential risks to establishing a safety profile and toxicity management guidelines for toxicity management during clinical development, followed by post-marketing surveillance;
- Regulatory strategies for assessment of the potential safety issues during drug development.
Please note: manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic.
Disclaimer: The views expressed are those of the authors and do not necessarily represent those of nor imply endorsement from the U.S. Food and Drug Administration or the U.S. government.
All Guest Editors declare no competing interests in the Research Topic subject.
The field of oncology has witnessed remarkable advancements in the development of anti-tumor monoclonal antibodies (mAbs) which have revolutionized cancer treatment strategies. Anti-tumor therapeutic antibodies can act on tumors via several mechanisms. They can directly target tumor cells either with an antibody-drug conjugate (such as ado-trastuzumab emtansine) or by inhibiting survival signaling pathways of cancer cells (EGFR inhibitors such as cetuximab and necitumumab). Some anti-tumor antibodies instead indirectly target cancer cells by increasing anti-tumor immune responses (immune checkpoint inhibitors such as nivolumab and pembrolizumab) or by modulating the functionalities of components within the tumor microenvironment (anti-tumor angiogenesis therapy such as bevacizumab).
Antibody-based anti-cancer therapy shows promising efficacy and generally has a better safety profile than small molecule-based anti-cancer drugs. However, many cancers do not respond or develop resistance to this form of therapy. While this loss of efficacy contributes to the majority of failures during therapeutic antibody development, therapeutic antibody-induced severe life-threatening toxicities are another critical attribute for such shortcomings, especially with the dramatic increase in the use of novel regimens of therapeutic antibodies. These novel regimens include but are not limited to (1) antibodies against novel targets, (2) combination therapy, e.g., multiple therapeutic antibodies, chemotherapy, small molecule targeted therapy combinations, and (3) new forms of therapeutic antibodies developed by modifications to the antibody structure, such as changes of glycosylation that are known to affect antibody-dependent cellular cytotoxicity (ADCC). Although a better understanding of the mechanism of action of therapeutic antibodies and a better design of clinical trials hold the key to limiting unintended toxicities, safety issues can still arise from other aspects of drug development, such as manufacturing a highly complex molecule such as a bi-specific or a tri-specific antibody.
With the enormous challenges inherent in developing an effective and safe therapeutic antibody, we hope this Research Topic will raise awareness and facilitate a rigorous discussion on the significant safety issues that arise during the development of anti-tumor monoclonal antibodies. Therefore, we invite Perspective, Review, Minireview, and Original Research manuscripts describing recent discoveries or thoughts related to safety issues in developing antibody-based anti-cancer therapy. We are particularly interested in the following subjects:
- Understanding the biology, structure, and function of anti-tumor antibodies to facilitate the development of safe and effective therapies;
- Preclinical models to assess safety profiles, including advances in three-dimensional tissue-engineered cell culture models that can potentially reduce or replace the usage of animal models;
- Developing clinical monitoring strategies to identify safety issues during the early stages of clinical trials;
- Lessons learned from successful clinical trials, or trials that failed due to safety concerns;
- Identification of biomarkers to predict the potential toxicity of anti-tumor antibodies;
- Understanding critical quality attributes and their impact on overall product safety;
- Identification of potential risks to establishing a safety profile and toxicity management guidelines for toxicity management during clinical development, followed by post-marketing surveillance;
- Regulatory strategies for assessment of the potential safety issues during drug development.
Please note: manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic.
Disclaimer: The views expressed are those of the authors and do not necessarily represent those of nor imply endorsement from the U.S. Food and Drug Administration or the U.S. government.
All Guest Editors declare no competing interests in the Research Topic subject.