From the journal RSC Chemical Biology Peer review history

28-Jul-2023

Dear Dr Bertozzi:

Manuscript ID: CB-REV-06-2023-000084
TITLE: Bringing enzymes to the proximity party

Thank you for your submission to RSC Chemical Biology, published by the Royal Society of Chemistry. I sent your manuscript to reviewers and I have now received their reports which are copied below. Please accept my apologies that this took longer than usual.

After careful evaluation of your manuscript and the reviewers’ reports, I will be pleased to accept your manuscript for publication after minor revisions.

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I look forward to receiving your revised manuscript.

Yours sincerely,
Claudia Höbartner
Associate Editor, RSC Chemical Biology
Institute of Organic Chemistry, University of Würzburg

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Reviewer 1

This is an extensive and well-structured overview of the use of targeted enzymes in the treatment of disease, which I believe is timely given the current advances in proximity-inducing pharmacology. The authors use historical context and provide concise and well-explained examples, with key references and clear figures, to illustrate the developments and the challenges within the field. I particularly enjoyed how the authors continuously and concisely draw comparisons between the different strategies, which I believe will be extremely useful to the reader to fully appreciate the benefits and shortfalls of each technique. Overall, this review was a real pleasure to read. I have provided some corrections and suggestions, which are detailed below.

Major comments
Page 8 Section 3.3.1 – It may be useful at the start of the section to give a short introductory sentence describing the mechanism of action and aim of targeted sialidases.
Page 8 Section 3.3.1 – It may be helpful to give a short description of BiTEs and how they work.
Page 9 Section 3.3.2 – A brief discussion of the challenges of targeting Muccins by classical therapeutic means could be useful here.

Minor comments
Page 9 Section 4. – The term blood-brain barrier is first used in the first paragraph and therefore the abbreviation BBB should be added here and referred to as BBB thereafter. In addition, enzyme replacement therapy and lysosomal storage disorders should be referred to as ERT and LSD here, respectively.
Page 11 Section 4.2 Final paragraph – Please consider rephrasing the last sentence to ¨it is important that the targeting agent and receptor are carefully selected¨.

Reviewer 2

This review by Gabrielle Tender and Carolyn Bertozzi provides an excellent overview of the history and impact of therapeutic enzymes, which are powerful tools in the modern repertoire of therapeutic biologics. In this work, they focus on the major limitation of therapeutic enzymes, namely the lack of (sub-)cellular specificity. In cancer therapy, non-specific administration of enzymatic therapeutics often leads to increased (on-target) toxicity caused by damage to non-malignant cells. In enzyme replacement therapies, limited cellular specificity reduces efficacy by limiting drug availability at the site of action.
This review focuses on ways to increase the cellular specificity of therapeutic enzymes and links this approach to the proximity concept of bispecific small molecules (such as PROTACs) or antibodies.
The review is intellectually stimulating, concise and well worth reading. My only suggestion would be to reduce the use of abbreviations to make it more accessible to a wider readership.

Reviewer #1
Remarks to author:
This is an extensive and well-structured overview of the use of targeted enzymes in the treatment of disease, which I believe is timely given the current advances in proximity-inducing pharmacology. The authors use historical context and provide concise and well-explained examples, with key references and clear figures, to illustrate the developments and the challenges within the field. I particularly enjoyed how the authors continuously and concisely draw comparisons between the different strategies, which I believe will be extremely useful to the reader to fully appreciate the benefits and shortfalls of each technique. Overall, this review was a real pleasure to read. I have provided some corrections and suggestions, which are detailed below.
1. Page 8 Section 3.3.1 – It may be useful at the start of the section to give a short introductory sentence describing the mechanism of action and aim of targeted sialidases.

Thank you so much for this suggestion. I have edited the text to include your suggestion:

“Antibody-sialidase conjugates were designed to cleave the immune inhibitory sialic acids specifically from cancer cells, thus promoting immune cell killing of the desialylated cancer cells. In our first-generation antibody-sialidase conjugate (T-sia 1)…”

2. Page 8 Section 3.3.1 – It may be helpful to give a short description of BiTEs and how they work.

I have added edited the text as follows:

“Sialidases have also been targeted specifically to the tumor-immune cell synapse through BiTEs, or bispecific antibodies that bridge a cancer cell and a T-cell and thus enhance T-cell killing of the target cancer cell, and CAR T-cells (Fig. 5c)”

3. Page 9 Section 3.3.2 – A brief discussion of the challenges of targeting Muccins by classical therapeutic means could be useful here.

Thank you for bringing this to my attention. I have added the following description:

“Mucins are difficult to drug with classical therapeutic and other bifunctional approaches, because they are a protein class comprised of repeated peptide domains highly modified with variable, branching, non-genetically encoded, and biosynthetically complex glycans, leading to an extended “bottle brush” conformation that can alter signaling and membrane biophysics.”

4. Page 9 Section 4. – The term blood-brain barrier is first used in the first paragraph and therefore the abbreviation BBB should be added here and referred to as BBB thereafter. In addition, enzyme replacement therapy and lysosomal storage disorders should be referred to as ERT and LSD here, respectively.

Thank you for catching this. I have made the relevant changes as well as switched to using “LSD” throughout the text.

5. Page 11 Section 4.2 Final paragraph – Please consider rephrasing the last sentence to ¨it is important that the targeting agent and receptor are carefully selected¨.

Done! Thank you.

Reviewer #2
Remarks to author:
This review by Gabrielle Tender and Carolyn Bertozzi provides an excellent overview of the history and impact of therapeutic enzymes, which are powerful tools in the modern repertoire of therapeutic biologics. In this work, they focus on the major limitation of therapeutic enzymes, namely the lack of (sub-)cellular specificity. In cancer therapy, non-specific administration of enzymatic therapeutics often leads to increased (on-target) toxicity caused by damage to non-malignant cells. In enzyme replacement therapies, limited cellular specificity reduces efficacy by limiting drug availability at the site of action.
This review focuses on ways to increase the cellular specificity of therapeutic enzymes and links this approach to the proximity concept of bispecific small molecules (such as PROTACs) or antibodies.
The review is intellectually stimulating, concise and well worth reading. My only suggestion would be to reduce the use of abbreviations to make it more accessible to a wider readership.

Thank you very much! I completely agree regarding the overuse of abbreviations. I have reduced the use of abbreviations for enzymes, drug classes, and diseases throughout the text.

16-Sep-2023

Dear Dr Bertozzi:

Manuscript ID: CB-REV-06-2023-000084.R1
TITLE: Bringing enzymes to the proximity party

Thank you for submitting your revised manuscript to RSC Chemical Biology. I am pleased to accept your manuscript for publication in its current form.

You will shortly receive a separate email from us requesting you to submit a licence to publish for your article, so that we can proceed with the preparation and publication of your manuscript.

All RSC Chemical Biology articles are published under an open access model, and the appropriate article processing charge (APC) will apply. Details of the APC and discounted rates can be found at https://www.rsc.org/journals-books-databases/about-journals/rsc-chemical-biology/#CB-charges.

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With best wishes,

Claudia Höbartner
Associate Editor, RSC Chemical Biology
Institute of Organic Chemistry, University of Würzburg


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