A Review on the Stability Challenges of Advanced Biologic Therapeutics

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The review article "A review on the stability challenges of advanced biologic therapeutics" is devoted to the study of various types of biomolecule-based drugs. The topic of the review is quite topical: at the moment, drugs based on biomolecules - antibodies, nucleic acids, etc. - are becoming increasingly important. At present, there are no recent reviews considering in detail the peculiarities of storage and handling of such drugs of all existing classes. There are separate reviews describing it for each class separately, especially for ADCs and antibodies. The concept of publication is worthy.

Nevertheless, there are a number of observations:

1. The review is very general. It brings together gene therapy, cell therapy, mRNA approaches, antibodies, ADCs and fusion proteins. The only thing these approaches have in common is that they are based on so-called biologics. Their properties, storage and applications are very different. Because of this, the authors do not manage to consider in detail all the peculiarities of handling each class of drugs, while much attention is paid to the general detailed description of each class. There is no general table or picture that would summarize the data or illustrate all these approaches and their features.
2. The introduction section duplicates the information for each class, which is then reported in full detail in each new section. Also, the paragraphing in this section is broken (lines 57-88), and the description of monoclonal antibodies would be logical to continue with the description of ADCs rather than fusion proteins. In addition, there are not enough references, such as in line 115, to give examples of vectors and references to relevant works. The paper as a whole lacks references to relevant examples.
3. Picture 1 is not informative. It would be better to highlight the gene fragment in the picture to indicate that it is defective, and then replace it with a picture with normal coloring of the double-stranded helix.
4. There are many typos in the text, e.g., capital letters in the wrong place, missing commas, periods.
5. There are very few tables summarizing the pros and cons of each method of drug stabilization in each section. Few illustrations on the topic of the review. Many of the pictures are of poor quality.

Overall, the review seems rather superficial, despite the impressive volume. In its current state, the review is more like an enumeration of disparate biologics with a superficial indication of their features. More illustrations and tables should be added to facilitate the understanding of currently existing biologics and their handling. In addition, in the section with each type of drugs it is necessary to add some conclusion, generalization, it is possible in the form of an illustration. It is also necessary to simplify navigation through the review, i.e. to make the numbering and titles of the sections more transparent.

I recommend that this article be accepted for publication after the above deficiencies have been corrected.

Comments for author File: Comments.pdf

Author Response

The review article "A review on the stability challenges of advanced biologic therapeutics" is devoted to the study of various types of biomolecule-based drugs. The topic of the review is quite topical: at the moment, drugs based on biomolecules - antibodies, nucleic acids, etc. - are becoming increasingly important. At present, there are no recent reviews considering in detail the peculiarities of storage and handling of such drugs of all existing classes. There are separate reviews describing it for each class separately, especially for ADCs and antibodies. The concept of publication is worthy.
Nevertheless, there are a number of observations:

Response: Dear reviewer, thank you for your positive response and recommending our manuscript for acceptance. We have accepted all your comments and made necessary updates in the manuscript and have highlighted them in yellow. Please see below a summary of changes made in response to the comments.

1. The review is very general. It brings together gene therapy, cell therapy, mRNA approaches, antibodies, ADCs and fusion proteins. The only thing these approaches have in common is that they are based on so-called biologics. Their properties, storage and applications are very different. Because of this, the authors do not manage to consider in detail all the peculiarities of handling each class of drugs, while much attention is paid to the general detailed description of each class. There is no general table or picture that would summarize the data or illustrate all these approaches and their features. 

Response: Thank you for the comment. We have created a figure to summarize the overall concept of the manuscript in the form of an illustration (Figure 1 in the revised manuscript).

2.    The introduction section duplicates the information for each class, which is then reported in full detail in each new section. Also, the paragraphing in this section is broken (lines 57-88), and the description of monoclonal antibodies would be logical to continue with the description of ADCs rather than fusion proteins. In addition, there are not enough references, such as in line 115, to give examples of vectors and references to relevant works. The paper as a whole lacks references to relevant examples.

Response: Dear reviewer, thank you for your valuable feedback. We have revised the introduction section to eliminate the duplication, providing only a brief overview of each class and leaving detailed discussions for their respective sections. The paragraphing also has been corrected to ensure the better flow. In addition, we agree with your suggestion and in response we have discussed the mAbs and ADCs together. All relevant references have been incorporated into the revised manuscript as suggested.

3.    Picture 1 is not informative. It would be better to highlight the gene fragment in the picture to indicate that it is defective, and then replace it with a picture with normal coloring of the double-stranded helix. 

Response: Thank you for your valuable feedback. As suggested, we have updated the figure to be clearer and understand the concept of gene therapy easily.

4.    There are many typos in the text, e.g., capital letters in the wrong place, missing commas, periods. 

Response: Thank you for the comment. We have proofread the manuscript and corrected the typos as needed.

5.    There are very few tables summarizing the pros and cons of each method of drug stabilization in each section. Few illustrations on the topic of the review. Many of the pictures are of poor quality.

Response: Thank you for the comment. As suggested by the reviewer, we have revised the tables with relevant information in all the sections. Please see the revised manuscript.

Overall, the review seems rather superficial, despite the impressive volume. In its current state, the review is more like an enumeration of disparate biologics with a superficial indication of their features. More illustrations and tables should be added to facilitate the understanding of currently existing biologics and their handling. In addition, in the section with each type of drugs it is necessary to add some conclusion, generalization, it is possible in the form of an illustration. It is also necessary to simplify navigation through the review, i.e. to make the numbering and titles of the sections more transparent. 
I recommend that this article be accepted for publication after the above deficiencies have been corrected.

Response: Thank you for the comment. We have revised the manuscript as per the reviewer’s suggestions. The numbering and titles of the sections have been updated throughout the manuscript to be more transparent.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The review paper provides a comprehensive and insightful examination of the stability concerns associated with advanced biological therapies, including gene therapy, cell therapy, mRNA therapeutics, monoclonal antibodies, fusion proteins, and antibody-drug conjugates (ADCs). The discussion on critical stability challenges and their impact on efficacy, shelf-life, and therapeutic success is well-articulated, and the review effectively outlines practical strategies to mitigate these issues. Overall, it is a well-written review paper that discusses advanced biological therapies. However, several revisions should be addressed before the manuscript is considered for publication:

1. Some sections discuss findings without referencing specific studies. In particular, Table 1 (List of Gene Therapy Products in Clinical Trials) lacks citations for the listed gene therapies. It is necessary to provide appropriate references for each therapy to support the claims.

2. The manuscript should ensure that abbreviations are introduced only once and used consistently throughout the text. For example, “LNP” appears multiple times in different contexts (Line 377, Line 386, and Line 398), this should be streamlined for clarity.

3. The description of lipid nanoparticles (LNPs) in Section 2.3 requires more precision. The authors state that “Lipid nanoparticles (LNPs) are improved delivery methods that protect mRNA, improve cellular absorption, and release it into target cells.” However, the actual function of LNPs is to facilitate the endosomal escape of mRNA rather than merely delivering it into cells. A more detailed explanation of this mechanism should be included in the manuscript.

4. The manuscript contains multiple typographical errors and minor language inconsistencies. A thorough proofreading is necessary to ensure clarity, precision, and grammatical correctness.

Author Response

The review paper provides a comprehensive and insightful examination of the stability concerns associated with advanced biological therapies, including gene therapy, cell therapy, mRNA therapeutics, monoclonal antibodies, fusion proteins, and antibody-drug conjugates (ADCs). The discussion on critical stability challenges and their impact on efficacy, shelf-life, and therapeutic success is well-articulated, and the review effectively outlines practical strategies to mitigate these issues. Overall, it is a well-written review paper that discusses advanced biological therapies. However, several revisions should be addressed before the manuscript is considered for publication:

Response: Dear reviewer, thank you for your positive response and recommending our manuscript for acceptance. We have accepted all your comments and made necessary updates in the manuscript. Please see below a summary of changes made in response to the comments.

1. Some sections discuss findings without referencing specific studies. In particular, Table 1 (List of Gene Therapy Products in Clinical Trials) lacks citations for the listed gene therapies. It is necessary to provide appropriate references for each therapy to support the claims.

Response: We have reviewed the content in the manuscript carefully and decided to remove the table from the manuscript.

2. The manuscript should ensure that abbreviations are introduced only once and used consistently throughout the text. For example, “LNP” appears multiple times in different contexts (Line 377, Line 386, and Line 398), this should be streamlined for clarity. 

Response: Thank you for the comment. We have reviewed the content in the entire manuscript and all the abbreviations have been used consistently throughout the manuscript.

3.    The description of lipid nanoparticles (LNPs) in Section 2.3 requires more precision. The authors state that “Lipid nanoparticles (LNPs) are improved delivery methods that protect mRNA, improve cellular absorption, and release it into target cells.” However, the actual function of LNPs is to facilitate the endosomal escape of mRNA rather than merely delivering it into cells. A more detailed explanation of this mechanism should be included in the manuscript. 

Response: Thank you for your insightful comment regarding the description of lipid nanoparticles (LNPs) in Section 2.3. We acknowledge that the original text lacked precision in explaining the function of LNPs. In the revised manuscript, we have incorporated a more detailed explanation of the LNP mechanism, with a particular focus on the crucial role of endosomal escape in mRNA delivery. The revised text clarifies how LNPs facilitate the release of mRNA into the cytoplasm, which is essential for its translation. We believe this enhancement provides a more accurate and comprehensive understanding of LNP functionality. Thank you again for this comment.

4.    The manuscript contains multiple typographical errors and minor language inconsistencies. A thorough proofreading is necessary to ensure clarity, precision, and grammatical correctness.

Response: We appreciate the reviewer’s observation. A thorough proofreading of the manuscript has been conducted, and all typographical errors and language inconsistencies have been corrected to enhance clarity, precision, and grammatical accuracy in the revised version.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors took into account my comments and made the necessary changes. The article can be published in its current form.