Monoclonal Antibodies

I'd say the main issue with monoclonal antibodies is making them "specific" enough. They typically target antigens on tumour cells that are expressed by some other cell types. This leads to binding to non-tumour cells which can cause side effects, as you mentioned.

There's a drug called Cetuximab, which is a mAb that targets EGFR. While this is expressed in certain tumours, this is also a marker of normal skin cells. As a result, this drug can cause serious rashes (the side effects aren't always as mild, as you seem to suggest).

On top of this, producing mAbs is a time-consuming and extremely expensive process - so there's also logistical reasons why they aren't the "silver bullet" drugs.

Also, mAbs are large molecules. Consequently, tissue and ECM penetration becomes an issue - especially with larger tumours (except for blood-based cancers of course). Maybe for some types of cancer the efficacy of mAbs will be high, but for others that may not be the case - so there isn't really a large supporting evidence base to put forward mAbs as "silver bullet" cancer therapies right now.

Maybe in the future? Who knows.

nice answer-thank you

The issue is that a lot of times you can't just target one thing with a drug/antibody and then kill the cancer. If it were that easy we would have cured many times of cancer a long time ago. Like with Herceptin that you've mentioned, it targets the Her2 receptor in cells to stop their constitutive activation, and the reason we use antibodies for this is because its easy to specifically target Her2 to the stop the cells proliferating, and so this is a really good treatment for people with Her2 positive breast cancer (until they become resistant). But for most cancers, the way the cancer cells are mutated is much more complicated. For example, a quarter of all cancers have mutated K-Ras, and K-ras itself is difficult to target, but its downstream effectors (of which there are loads- MEK, ERK, Rac, Raf, Rho the list goes on) are much more druggable and people have tried doing this, but its wayyy too toxic to be a good treatment because of how vital these pathways are in general cell maintenance. There's no point in killing the cancer if you kill the patient too. And we could try and target these downstream effectors much more specifically with antibodies so they don't affect the healthy cells so much (e.g. specific for the mutant protein in the cancer cells) but we can't do this because these mutant proteins are inside the cell, and antibodies don't enter cells until they are phagocytosed and degraded along with the antigen (it works with Her2 because its on the outside of the cell). So this is where personalised medicine and gene therapy comes in, which would in theory act in a much more targeted way like antibodies, but allow you to target mutations that affect intracellular proteins. So its much much more likely that the 'silver bullet' you've mentioned will be specific personalised treatments, where you get genetically tested, and then the drugs/gene therapy you are given are tailored to your specific type of cancer (because every patient's cancer is so genetically different), rather than mAbs.

We should also note that cancer 'evolves'. Cancers are not dynamic, but can grow resistant to therapy. Hence one 'silver-bullet' is often not the answer. Even if we knockout the gene the cancer depends upon (its oncogene), which will result in marked tumour reduction, because tumours replicatate at such a high frequency they are likely to develope go-arounds. This is why drug resistance in cancer is a significant issue.

I'd say the main issue with monoclonal antibodies is making them "specific" enough. They typically target antigens on tumour cells that are expressed by some other cell types. This leads to binding to non-tumour cells which can cause side effects, as you mentioned.

There's a drug called Cetuximab, which is a mAb that targets EGFR. While this is expressed in certain tumours, this is also a marker of normal skin cells. As a result, this drug can cause serious rashes (the side effects aren't always as mild, as you seem to suggest).

On top of this, producing mAbs is a time-consuming and extremely expensive process - so there's also logistical reasons why they aren't the "silver bullet" drugs.

Also, mAbs are large molecules. Consequently, tissue and ECM penetration becomes an issue - especially with larger tumours (except for blood-based cancers of course). Maybe for some types of cancer the efficacy of mAbs will be high, but for others that may not be the case - so there isn't really a large supporting evidence base to put forward mAbs as "silver bullet" cancer therapies right now.

Maybe in the future? Who knows.

We should also note that cancer 'evolves'. Cancers are not dynamic, but can grow resistant to therapy. Hence one 'silver-bullet' is often not the answer. Even if we knockout the gene the cancer depends upon (its oncogene), which will result in marked tumour reduction, because tumours replicatate at such a high frequency they are likely to develope go-arounds. This is why drug resistance in cancer is a significant issue.