Monday, May 20, 2024

Journal Club: Paul et al. (2024) Cancer Therapies with Antibodies


It may seem daunting to write - or read - a review article with a scope as broad as "Cancer therapy with antibodies," but that's what we have this month from Paul et al.    Find it in Nature Reviews Cancer,

It's a major achievement, coming in at 28 pages and nearly 300 citations.

The focus of Paul et al. is on cancer, but see also a new article in Nature by Desautels et al., "Computationally restoring the potency of a clinical antibody against Omicron," here.   Writing, "...Our results suggest that computational approaches can optimize an antibody to target multiple [viral] escape variants, while simultaneously enriching potency."

AI Corner

Here's an AI summary of Paul et al. provided by Chat GPT 4o:

Review of "Cancer Therapy with Antibodies"

1. What are the three main types of antibody-based cancer therapies discussed in the article?

Answer: The article reviews three main types of antibody-based cancer therapies:

  • Monospecific Antibodies: These are full-length immunoglobulins that target a specific antigen on cancer cells, leading to cell death through mechanisms like antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC).

  • Bispecific Antibodies: These antibodies are designed to bind two different antigens. T cell engager bispecific antibodies (TCEs) crosslink a cancer cell with an effector T cell, activating the T cell to kill the cancer cell. Non-T cell-engaging bispecific antibodies bind two different antigens on the same cancer cell, blocking proliferation signals and activating immune effector cells.

  • Antibody–Drug Conjugates (ADCs): These involve antibodies linked to cytotoxic drugs, toxins, or radioactive isotopes. ADCs deliver toxic payloads directly to cancer cells, minimizing damage to normal cells.

2. How have advancements in antibody engineering improved cancer therapies?

Answer: Advancements in antibody engineering have significantly improved cancer therapies by enhancing specificity, reducing immunogenicity, and increasing therapeutic efficacy. Key developments include:

  • Chimeric and Humanized Antibodies: Initial mouse antibodies were modified by grafting human antibody constant regions to reduce immune responses. Further humanization involved grafting only the complementarity-determining regions (CDRs) of mouse antibodies onto human frameworks.

  • Fully Human Antibodies: Technologies such as human antibody phage display and transgenic mouse models have enabled the production of fully human antibodies, reducing the risk of immune reactions and improving clinical outcomes.

  • Fc Engineering: Modifying the Fc domain of antibodies has enhanced their interactions with Fc receptors, improving ADCC and ADCP. Examples include afucosylation and amino acid substitutions to increase FcγR binding.

3. What are the primary mechanisms of action for therapeutic antibodies in cancer treatment?

Answer: Therapeutic antibodies employ several mechanisms to target and kill cancer cells:

  • Direct Antagonism: Monospecific antibodies bind to and block receptors critical for cancer cell survival and proliferation, such as HER2 and EGFR.

  • Immune Activation: Immune checkpoint inhibitors block proteins like PD1, PDL1, and CTLA4 that suppress T cell activity, thereby reinvigorating the immune response against cancer cells.

  • Cytotoxic Payload Delivery: ADCs internalize upon binding to their target antigen and release cytotoxic drugs within the cancer cells, causing cell death.

  • T Cell Redirection: Bispecific T cell engagers (TCEs) connect cancer cells with T cells, activating the T cells to release cytotoxic granules and kill the cancer cells.

4. What are the challenges associated with antibody-based cancer therapies, and how are they being addressed?

Answer: Challenges with antibody-based cancer therapies include:

  • Immunogenicity: Early mouse-derived antibodies triggered immune responses, limiting their efficacy. This has been addressed by developing chimeric, humanized, and fully human antibodies to reduce immunogenicity.

  • Toxicity: Immune checkpoint inhibitors can cause immune-related adverse events (irAEs), such as skin rashes, diarrhea, and thyroid disorders. These are managed with immunosuppressants and careful monitoring.

  • Efficacy in Solid Tumors: Bispecific T cell engagers have shown less success in solid tumors compared to hematological malignancies. Ongoing research and clinical trials aim to overcome this by targeting novel antigens and optimizing dosing strategies.

5. What future directions and emerging research are highlighted for improving antibody-based cancer therapies?

Answer: The article highlights several future directions and areas of emerging research:

  • Next-Generation Antibody Formats: Research is focused on developing more effective bispecific antibodies and optimizing ADCs with novel linkers and cytotoxic drugs to enhance efficacy and reduce off-target effects.

  • Personalized Therapy: Advances in understanding tumor biology and immune responses are paving the way for personalized antibody therapies tailored to individual patient profiles.

  • Combination Therapies: Combining antibody-based therapies with other treatment modalities, such as chemotherapy, radiotherapy, and other immunotherapies, is being explored to improve treatment outcomes.

  • Novel Targets: Identifying and targeting new antigens and immune checkpoints are ongoing areas of research, aiming to broaden the applicability and effectiveness of antibody-based cancer therapies.