Monoclonal Antibodoies At The Forefront of War With Cancer

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Monoclonal antibodies (mAbs) are laboratory-produced molecules that are designed to mimic the natural antibodies produced by the immune system. Antibodies are proteins produced by specialised immune cells called B cells in response to the presence of foreign substances, such as pathogens or abnormal cells.

Monoclonal antibodies, as the name suggests, are a type of antibody that is derived from a single clone of B cells. They are designed to target and bind to specific antigens present on the surface of cells or pathogens. This specificity allows monoclonal antibodies to recognize and bind to their target with high precision.

The production of monoclonal antibodies involves a multi-step process. When highly simplified the method can be boiled down to,

Step: 1- A mouse or other animal is immunised with the desired antigen.

Step 2- The B cells that produce antibodies against the antigen of interest are then isolated and fused with cancer cells to create hybridoma cells.

Step 3- These hybridoma cells have the ability to continuously produce the specific antibody of interest.

Once the hybridoma cells are generated, they can be cultured in the laboratory to produce large quantities of the desired monoclonal antibody. The resulting monoclonal antibodies can be purified and used for various applications, including diagnostics, research, and therapeutic purposes. While in earlier periods this technique hadn’t been perfected to the extent of today causing issues like Immunogenicity and poor induction of immunity, poor action/ failure, current research has reduced the incidence of such cases by an incredible margin.

Main Body/ How it works:- One of the primary ways this system works for example is in the case of cancer where mAbs are being very useful in experimental treatment in which these antibodies cause tumour cell death by blocking the signalling of growth factor receptors. By binding to their specific target growth factor receptors, mAbs disrupt the pro-tumor growth and survival signals. They achieve this by manipulating the activation state of the receptors or preventing ligand binding. For instance, in cancers where the epidermal growth factor receptor (EGFR) is overexpressed, signalling through EGFR promotes tumour cell proliferation, migration, and invasion. An anti-EGFR monoclonal antibody called Cetuximab induces apoptosis in tumour cells by obstructing ligand binding and receptor dimerization.

In addition, there are currently a multitude of other ways that mAbs are employed in cancer therapy, including antibody-drug conjugates, targeting pro-tumorigenic compounds in the microenvironment, bispecific T cell engagers (BiTEs), and immune checkpoint inhibitors.

Early efforts in the development of mAb therapies focused on enhancing the direct cytotoxic effects on targeted tumour cells. Clinically beneficial anti-tumor activity has been accomplished by conjugating mAbs with different effector molecules that cause tumour cell death after antibody binding and internalisation. Effector molecules may include cytotoxic drugs, immunotoxins, and radionuclide agents.

- The most important consideration in antibody–conjugate design is the selection of the target, which is the main determinant of anti-tumor activity and selectivity. In addition, targets must be capable of internalisation upon antibody binding in order to release the drug. Brentuximab vedotin became the first antibody–drug conjugate (ADC) to be FDA approved in 2011

- The second class of agents that can be delivered to tumour cells via conjugation to mAbs are biologic toxins, However, this method has proven difficult due to the extreme potency of the toxins, causing unacceptable toxicity in patients. Pseudomonas exotoxin A (PE) and ricin toxins are the most common toxins in targeted cancer therapy and remain under clinical investigation. To date, only moxetumomab pasudotox, a CD22 targeted mAb linked to PE for hairy-cell leukaemia, has received FDA approval.

- The last category of antibody-based compound delivery involves radionuclides. Radioimmunotherapy uses a mAb labelled with a radionuclide as a form of targeted radiation therapy. Currently, only two radio immunotherapies have been FDA approved: yttrium-90 (90Y)-ibritumomab tiuxetan and iodine-131 (131I)–tositumomab. Both agents utilise a mAb specific for CD20 to deliver either yttrium-90 or iodine-131 to lymphoma cells. Unfortunately, radio immunotherapies can cause life-threatening systemic toxicity and solid tumours are often inaccessible or insensitive. Since the practicalities of preparing and delivering these agents have proved complex they have not seen widespread use, and tositumomab was discontinued by their parent company.

Targeting the tumour microenvironment has proven to be clinically effective in inhibiting pro-tumorigenic processes. Vascular endothelial growth factor (VEGF), which promotes angiogenesis, has been a significant target. The monoclonal antibody bevacizumab blocks VEGF from binding to its receptor, inhibiting angiogenesis, and is approved for treating various cancers. Targeting VEGFRs using antibodies such as ramucirumab (VEGFR2) and icrucumab (VEGFR1) has also shown promise. The monoclonal antibody fresolimumab, which targets TGF-β, is undergoing clinical trials. Combining tumour-targeted therapy with monoclonal antibodies that target the tumour microenvironment presents a compelling strategy to synergistically inhibit pro-tumorigenic processes.

Recent successful monoclonal antibody (mAb)-based strategies have shifted focus from targeting tumour antigens to enhancing the anti-tumor capabilities of immune cells. One approach is the development of bispecific T Cell Engager (BiTE) antibodies, which simultaneously target a tumour antigen (e.g., CD19) and the activating receptor CD3 on T cells. BiTEs promote direct targeting of tumour cells while recruiting cytotoxic T cells to the tumour microenvironment. Even at significantly lower doses than the parent mAb alone, BiTEs have shown tumour regression. Blinatumomab, a CD19-CD3 BiTE, has demonstrated significant clinical benefits in patients with acute lymphoblastic leukaemia and received FDA approval in 2017.

As mentioned earlier, The most well-known and promising type of mAb therapy for cancer is the blockade of immune checkpoints. Immune cell activation and regulation is a highly complex process that must integrate a variety of costimulatory and coinhibitory signals in order to control immune cell responses to antigen. Immune checkpoints are inhibitory receptors and pathways that are responsible for maintaining self-tolerance and modulating immune responses in order to curtail collateral tissue damage, as such  Monoclonal antibody-based immune checkpoint blockade (ICB) therapy has been developed to target specific molecules involved in regulating immune responses. The first ICB therapy, Ipilimumab, targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), was approved for melanoma treatment in 2011. Ipilimumab is being evaluated in clinical trials for other cancer types as well. Another important immune checkpoint is programmed death receptor-1 (PD-1), which is expressed on various immune cells and plays a role in regulating T cell function. Tumor cells often upregulate the PD-1 ligand, PD-L1, to suppress tumor-infiltrating lymphocytes (TILs) and evade immune responses. ICB therapies targeting PD-1 and PD-L1 have shown promising results and are actively investigated in clinical settings. These monoclonal antibody approaches aim to enhance anti-tumor immune responses and have the potential to improve cancer treatment outcomes.

As of this writing something incredible is happening, mAbs against the immune checkpoints CTLA-4, PD-1, and PD-L1 have received numerous FDA approvals and are used as first-line therapies for the treatment of certain solid tumours.

Despite the success of monoclonal antibody (mAb) therapy in cancer treatment, the emergence of clinical resistance to these agents remains a significant obstacle. The majority of patients do not exhibit a response to mAb therapy, and even those who initially respond often develop refractory disease within a year. Resistance to therapy can be categorised as either innate (primary) or acquired (secondary), with distinct mechanisms involved in each scenario. Innate resistance occurs when tumor cells possess pre-existing mutations that make them resistant to mAb therapy before treatment even begins. Acquired resistance, on the other hand, arises as a result of immune selection pressure and the shaping of the tumor during the course of therapy. Through preclinical models and clinical trials, numerous mechanisms of resistance to mAb therapy have been elucidated, including mutations in the target of the antibody, activation of alternative growth signaling pathways, epithelial to mesenchymal transition (EMT), and impaired responses of immune effector cells. These findings highlight the intricate nature of resistance mechanisms and underscore the importance of further research to overcome these challenges and enhance the effectiveness of mAb therapy in cancer treatment.

As such, it is essential for mAbs to be used in combination medicine; while mAb has success as a monotherapy in some patients, treatment paradigms are trending towards employing them as combinations with chemotherapy, radiation, molecularly targeted drugs such as tyrosine kinase inhibitors, other antibodies against the same target, immune checkpoint inhibitors, vaccines, and/or cellular therapies. These many combination strategies are currently undergoing both preclinical investigation and clinical trials, and this vast field is more exhaustively covered elsewhere. It is now widely recognized that the mechanism of action of monoclonal antibodies includes an immune effector cell component. In particular, cetuximab efficacy has been partly attributed to ADCC, which can link innate and adaptive anti-tumor immune responses.

Likewise, the use of ICB in breast cancer in order to enhance anti-HER2 mAb therapies is a promising strategy. In fact, preclinical evidence suggests that resistance to trastuzumab monotherapy can be overcome by combination with ICB. Based on those results several clinical trials were formed to investigate the relationship between ICB and HER2-targeted mAbs; these tests showed a positive synergy for the same.

Conclusion

On a concluding note, Monoclonal antibody (mAb) therapy has emerged as a significant treatment modality for cancer, but many aspects of its mechanisms and clinical relevance are still poorly understood. Despite notable clinical successes, therapeutic resistance remains a major challenge. Future research should focus on comprehensively analyzing the mechanisms of mAb action to identify new approaches that can enhance clinical efficacy. One promising avenue is augmenting antibody-dependent cellular cytotoxicity (ADCC) activity, which has been found to play a crucial role in mediating mAb responses. Combining tumor-targeted mAbs with immune checkpoint blockade (ICB) has shown promising results, providing opportunities to maximize the clinical benefits of mAb therapy. Mutations in the antibody target and associated signaling pathways are important biomarkers for mAb efficacy and resistance. Future strategies should incorporate inhibitors targeting these alternative signaling pathways to overcome resistance. The treatment paradigms involving monoclonal antibodies are continuously evolving and hold the potential to offer curative therapy for many cancer patients.