Tag Archives: tumor

Using Antibodies as vaccine delivery vehicles

Antibodies are glycoprotein molecules synthesized by plasma cells (mature, activated B cells) with the capacity of binding to any potential antigen epitope. For a review of lymphocytes and how they are activated, see this link where you will find more information about antibody production in response to ’challenge’.


An (IgG) antibody with basic structural features labeled

Antibodies are the natural products of these plasma cells and function in a variety of ways to effect immunity. Most basically, they bind and may interrupt the function of the target molecules or trigger a response disadvantageous to the pathogen. In addition, a number of other functions are mediated by these molecules, including recruitment of complement and of phagocytic cells that will digest and inactivate the cell / antigen.

Therapies, such as vaccines, are designed to separate and eliminate the disease-causing elements of a pathogen from those that generate an immune response, thereby initiating a normal immune response to antigens without the dangerous exposure to live pathogens. Most often, these are prophylactic vaccines that initiate the development of immune ’memory’ prior to any disease exposure.

In some cases, therapeutic vaccines do much the same job, but are used to ’jump-start’ an immune response that has failed to initiate naturally for some reason (this may be because the target of the therapy is very similar to ’self’ as is the case with cancer), or because a long-term, chronic disease has fooled the body into tolerating an unwanted condition.

Additionally, some molecular therapies provide passive immunity by administering exogenous antibody that fulfills these functions. A weakness of these therapies is that, by providing pre-made antibody, potential antigens are blocked and no endogenous antibody response will be elicited.

A final use of antibodies, to be elaborated further here, is to provide targeted delivery of toxins to pathogens or infected cells or to deliver antigens to the immune system.

Purpose: to trigger / amplify immunity to an ongoing infection or disease


1. Target protein or cell – what cell and what protein on that cell should be targeted to elicit the desired immune response?

2. How to get antibody to the site where target cells are present?

3. What is the desired response / activity of the target cell?

4. What, if any, molecule is being delivered to these cells?

5. Lastly, how can efficacy be measured and what are the objective endpoints that will be used to determine whether therapy is effective?

Although this antibody is not currently in use therapeutically, I will use, as an example, one that I made while working for a biotech company some years ago.


An antibody with an antigen conjugated to the Fc portion

The antibody we used specifically bound to the macrophage mannose receptor (MMR) expressed by macrophages and the similar phagocyte cells, dendritic cells. Natively, this protein binds to a sugar, mannose, that is commonly charged to protein molecules. Once bound, the MMR will direct receptor-mediated endocytosis of the bound protein and deliver it to endolysosomes for processing and presentation upon MHC class II molecules (see animation below). As explained in the link, processing and presentation lead to the activation of T Cells and the resulting immune response.

Using an antibody that targets this molecule (MMR), a target compound can be fused to the antibody (chemically or genetically) leading to the precise delivery of this compound into the cell and the generation of a response. The antibody will guide the (tumor) antigen to the phagocytic cell. In this way, the antibody serves only as a vehicle. This vehicle takes its passenger, the antigen that we would like to generate an immune response against, and inserts this antigen into the processing and presenting apparatus of these ‘professional’ antigen presenting cells.

Animation of Antibody delivering a Target Antigen to an APC:

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Posted by on December 26, 2013 in Uncategorized


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Devilish Tumors


     You poor devil

RadioLab recently updated and rebroadcast their Tumors episode (RL link). This includes a story about President Grant’s tumor kept in a cigarbox in museum archives and one about the transmissible facial tumor plaguing Tasmanian Devils. The tumor, known as Devil Facial Tumor Disease (DFTD) is a rare case of an infectious cancer. This is the one that I wanted to think about some more.

What do we know about tumors? How do they arise? Why is cancer so much more prevalent today than ever before? What makes these Tasmanian Devil tumors especially nasty?

What do we know about tumors?

Actually, quite a lot. And many new therapies are very successful – especially those that target very specific kinds of tumors. In 1963 Todero and Green   ( established both a cell line and a precise methodology for growing cells in culture that permitted researchers the ability to recognize specific changes in cells grown in culture – changes such as becoming non-responsive to the presence of other cells that should control cell division.


                                              30 years of p53 research

Over the years a number of tumor suppressor proteins and proto-oncogenes have been identified. These are the proteins responsible for restraining cell cycle in the event of DNA damage. Among these is p53, the most frequently altered protein in cancer. It was originally identified in 1979 and has since been shown to arrest cell cycling in the event of DNA damage, initiate repair protocols and start a ‘countdown’ to self-destruction (apoptosis).

A number of additional mutations have been defined in proteins that either promote cell cycle progression (proto-oncogenes) or arresting cell cycle progression. Each of these proteins may be mutated in a different way, but the outcome is always the same: cells are pushed through their cycle despite the presence of DNA damage.Image

Beyond this, more processes have been found to contribute to tumor success. Some tumors promote angiogenesis (the growth of new blood vessels) to feed the tumor. Some have mutations that allow them to break off of the main tumor mass and survive in the blood or lymph and migrate to new areas. Some tumors perform tricks to escape recognition by the immune system.

In time, successful tumors may do all of these things. And how can they mutate so quickly and skillfully? It all goes back to p53. When a cell doesn’t slow down and correct errors in its DNA – and when it does not self-destruct when these errors are too damaging, the cell is free to mutate again and again. Each mutation is like a new child that either does better or worse in its environment, with only the successful ones living to spread their genes.

How do they arise?

Tumors arise when DNA damage occurs in just such a way that it escapes notice by the cell and starts to multiply. Actually, we think that a lot of tumors start up, but get weeded out by our immune system again and again. The ones we see are those that were successful enough to evade our defences and grow up. (immune surveillance:

Why is cancer so much more prevalent today than ever before?

Because we live so much longer. The increase in cancer rates does not come from cancer becoming worse over the years, but comes from the fact that we live long enough to get it


      We’re getting old … Unfortunately, that means we’re getting cancer too



What makes these Tasmanian Devil tumors especially nasty?

Transmissible tumors are rare because of the conditions required to allow for them are also very rare. In the case of DFTD the stars aligned in just the right way to allow this to occur.

The first requirement is that a tumor must have evolved sufficiently to be able to spread throughout the body of the initial host and be expressed on the face of this animal.

Second, this tumor was amazing in that it could start growing even in new animals if cells should be transferred from one to another. This may have something to do with the uniformity of the devil population and/or the way that these tumors ‘hide’ cellular markers that would otherwise expose them as bad/ foreign cells. The latter of these explanations is supported by data such as: pnas “reversible epicene tic down-regulation of MHC by devil facial tumor…” Siddle et al vol. 110 no. 13

(my question now is: don’t these devils have NK cells that should eliminate these MHCI-deficient cells?)


Perhaps most importantly, these tumors affect animals that are naturally aggressive towards other members of their species in both feeding and sex. Because devils bite one another so often, they provide just the right opportunity for cells to jump from one animal to another.

There is a similar case of a canine transmissible tumor (“tumor cells spread canine cancer” in the scientist, August 10, 2006 by Melissa lee Phillips.) but other than that, these types of tumors are not often seen.

Altogether, this is a fascinating case that illustrates some peculiarities of tumors, DNA damage control and immunology.

The devastating effect of this tumor epidemic is that it has precipitated a dramatic decline in devil numbers now making them endangered of extinction.


Visit the ‘Save the Tasmanian Devil’ website for more information about their condition. (:



Posted by on October 27, 2013 in Uncategorized


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Cancer and the immune system (briefly)

Macrophage engulfing bacteria

 What a breath of fresh air! A good old friend of mine, who I met while in graduate school and is now living in Mexico city has been working on a couple of papers that he is submitting to some English language journals. I’ve only read one of them so far – it’s an interesting review of work that suggests that tumors actively co-opt processes of the immune system to their own advantage. His spoken English is quite good, but it’s another thing altogether to write well for a scientific publication. Lucky for me, I guess, because it gives me a way to be involved.

It is well established that the immune system functions to prevent tumor formation known as immunosurveillance. This is pretty consistent with the basic role of defending the self against any non-self target it encounters. If you’re unfamiliar with immunology and want one thing to learn, that’s it: The immune system is there to recognize a black and white world of self vs non-self. The details are complicated, but it’s fairly well worked out that through a series of positive and negative selection events you can train your immune cells to be tolerant of you (self), but reactive against anything new (non-self).

With respect to cancer, it’s important to recognize that these cells start out as self and are ignored by the immune system, but they change in a way that they are not acting the way they should. The problem for the immune system is that these changes typically just mean that the cells are acting abnormally, but they don’t necessarily look foreign. Despite this, we know that animals that lack a functional immune system will succumb to tumors at higher frequency earlier in life than those with competent immunity.

My friend’s article extends this relationship beyond immunosurvellience and suggests that the tumor cells undergo a selection process by the immune system that will eliminate weaker cells, leaving only cells that either escape the notice of the immune system entirely or are extraordinarily resistant to attacks. Further, he describes that the remaining cells will often co-opt signals of the immune system to advance their own function and survival. 

I look forward to finishing up this paper and hope to be able to point you toward a journal that it is published in sometime in the near future. Until then, it’s so refreshing to think about immunology again. I miss it.


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Posted by on November 3, 2012 in Uncategorized


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Cell Cycle and Cancer

Cell Cycle in intimately connected to cancer because, in essence, cancer is a disease of cell cycle dysregulation. The purpose of regulating the cell cycle is to maintain genomic integrity, therefore the checkpoints of cell cycle progression specifically interrogate the DNA’s suitability to replicate, to divide and to be assorted into new, ‘daughter’ cells.


If a cell replicates DNA when there is damage to the DNA, then poor copies are perpetuated. If a cell commits to division when there is DNA damage, the same result might ensue – i.e. daughter cells may receive poor copies of the DNA. If a cell divides when chromosomes are not properly assorted then neither cell is healthy.

All three mechanisms have the same goal: ensure high fidelity copying.

With cell cycle checkpoints intact, cells can only pass when their DNA is in good condition or when chromosomes are being handled properly. The result is one healthy cell gives rise to two healthy cells. If a cell reaches a checkpoint and damage is detected, then the cell ‘arrests’ cycle progression for a short period of time. During this arrest, the cell has the opportunity to rescue the DNA and resume cycling. If this does not happen, then the cell is triggered to commit apoptosis –  cellular suicide. In this was, the cell gives its life for the good of the organism.

In this way, the cell is very analogous to a bee stinging an intruder. Although the bee will die now, it has contributed to the good of the colony in its sacrifice. After all, the worker bee cannot reproduce herself, her genetic heritage is intimately tied to the fate of the colony and its queen. Similarly, the cell dies to preserve the organism against what might be a harmful alteration / mutation. And, like the bee, this cell likely could not reproduce by itself anyway, it’s genetic heritage is tied to that of a larger body where only the gonads produce reproductive cells.

When cell cycle checkpoints are not functional, poor copies of DNA / cells get through. Furthermore, these cells are now inherently unstable because they have a compromised checkpoint, and additional errors may accumulate. Sometimes these errors disrupt other regulators of cell cycle, leading to a compounded problem. Over time, these cells may develop into cancerous cells.

The other point of cell cycle regulation is in the midst of mitosis, during metaphase. At this time, the cell has bound the chromosomes with spindle fibers that attempt to shorten and pull the chromosomes to a flat plane in the middle of the cell called the metaphase plate. The checkpoint here is to find out whether every single chromosome has attached to each side and each daughter cell will get the correct number. If this fails, cells will have incorrect distributions of the chromosomes and are unlikely to survive. Further, if these cells did survive, they would never be able to correct the error.

Here, the bee analogy would be too strained to continue, but it is not too difficult to see that when a cell disentangles itself from preserving the health of the body and instead looks only after its own short-sighted interests that these cells will grow and compete directly against the rest of the body for space and resources. Initially, when a tumor is small, this may have little consequence, but as a tumor becomes larger or more dispersed in the body, this selfishness can severely impact the larger organism, ironically (for the cancer cell) undermining even the tumor’s self interest.

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Posted by on October 14, 2012 in Education, Uncategorized


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