Background

The gp120-mediated autoimmune model asserts that the collapse of the immune system known as AIDS is caused by the combination of gp120, a coat protein on HIV, and antibodies to gp120 that are created by a single clone (type) of B cells. This combination shuts down the T₄ cells which are necessary to maintain the immune system. There are two possibilities for preventing this cycle - eliminate gp120 or eliminate the antibody to gp120.

Most current AIDS therapies attempt to stop HIV from reproducing. This leads to fewer HIV particles in the body, and thus to fewer infected cells. Since these are the two sources of gp120 being shed into the blood, current therapies reduce the amount of gp120 present. These therapies can improve the overall level of health and extend people's lives. Unfortunately, these drugs are complicated to administer, expensive, have severe side effects, and fail entirely for many people. As not all virus is eliminated from the body, there is still enough gp120 shed to shut down significant numbers of T₄ cells. Furthermore, HIV rapidly mutates around whatever drug is being used to prevent its reproduction.

The Structure and Function of Immudel-gp120

Instead of eliminating gp120, the Institute for Applied Biomedicine has developed a drug, Immudel-gp120, designed to eliminate the antibodies to gp120. Antibodies are made by B cells. Immudel-gp120 is designed to specifically kill those B cells which make antibodies to gp120 without harming other cells in the body. Once dead, these B cells would obviously not produce antibody. Therefore the level of antibodies to gp120 would fall, crosslinking and targeting of T₄ cells by the immune system would end, and the T₄ cells could carry out their essential tasks.

The rest of the B cells, those not sensitive to gp120, would continue making antibodies to other substances as usual. In addition, with healthy T₄ cells, T₈ cells would continue to function and control the HIV infection. Since gp120 would still be present, Immudel-gp120 would have to be given with low doses of Interleukin-2. This is a safe compound, a natural immune system hormone, previously used with benefit for AIDS treatment. Interleukin-2 allows T₄ cells to function normally in the presence of gp120 (as long as antibody is not also present).

The structure of Immudel-gp120 is based on the fact that B cells must internalize gp120 both to start and to continue making anti-gp120 antibodies. The drug will consist of two parts: a slightly modified gp120 attached to a highly specialized toxin. The B cells recognize the gp120 portion and internalize the entire drug, thus poisoning themselves.

Although many toxins could be used for this purpose, we have prepared and tested Immudel-gp120 using receptorless diphtheria toxin. Diphtheria toxin is so potent that only one molecule can kill a cell (119). "Receptorless" means that the toxin has no receptor with which to get into any human cell (117, 118). Without a way to get into cells, receptorless diphtheria toxin is essentially harmless.

Attaching modified gp120 to the toxin lets the toxin get into any cells which internalize the modified gp120. Although different B cells can bind to different sections of gp120, CD4 always binds to one specific site on the gp120. (120) We have modified this site so that Immudel-gp120 is incapable of binding to CD4. This means that Immudel-gp120 cannot bind to, and therefore cannot be specifically internalized by, T₄ cells and macrophages. (There is no evidence suggesting that nerves, sperm, and gut cells can internalize gp120.) This modification will also decrease the required dose, since Immudel-gp120 will not be bound by non-target cells, leaving more available to kill B cells.

Advantages to Immudel-gp120

• Treatment of AIDS: With Immudel-gp120, we believe that the collapse of the immune system characteristic of AIDS can be held off indefinitely in people who are HIV-positive and can be reversed in people who have AIDS. Our expectation is that Immudel-gp120 could cure advanced cases of AIDS if the person could survive the opportunistic infections for the one to two months required for the immune system to recover. It has been shown that the immune system can recover fully even after considerable damage, given sufficient time.

• Restoration of T₈ Cell Function: Immudel-gp120 would also enable the T₈ cells to function. T₈ cells are the only things known which are able to selectively target and kill infected cells. Therefore they are vital in controlling an HIV infection, as well as maintaining normal immune function.

• Monthly Injection: Immudel-gp120 would be administered only once a month by intramuscular injection. Intramuscular injections are easy to administer. Insulin-dependent diabetics regularly perform such injections on themselves. This represents a considerable advance over current treatment which require complicated regimens of pills taken at precise times with differing types of food or drink. These complicated regimens are extremely difficult for many people to maintain.

• Inexpensive Manufacturing Process: Immudel-gp120 should be inexpensive to produce, when done in bulk. It can be made by a much simpler, less expensive process than the current AIDS treatments. Obviously, it is difficult to estimate the cost to the patient. However, it is almost certain to cost much less than current AIDS therapies, which cost $1,000 per month or more in combination.

• Immune to Drug Resistance: Since Immudel-gp120 is targeted at human cells rather than the virus, HIV cannot become resistant to it. Drugs that directly attack HIV naturally select for resistant strains, since only resistant strains are able to reproduce. But since Immudel-gp120 does not attack HIV, no opportunity exists for the virus to mutate around it. If a B cell were to mutate and become incapable of binding to the toxin it would also be incapable of binding or making antibodies to gp120. This is still the desired outcome.

• Usable in Combination: Likewise, since existing AIDS therapies impact a completely different part of the disease, use of Immudel-gp120 should not affect the efficacy of any other drug. Similarly, resistance to any other drug should not affect the efficacy of Immudel-gp120. In other words, Immudel-gp120 would not cause cross-resistance, as other AIDS drugs often do to each other. We don't know whether Immudel-gp120 would be sufficient on its own to control all the symptoms of HIV infection, but it will certainly not interfere with other treatments.

• AIDS Wasting and Dementia: Finally, there is strong evidence that Immudel-gp120 could prevent or mitigate both AIDS wasting syndrome and AIDS dementia. We are currently writing a scientific article citing the evidence supporting this claim. Please contact us for an explanation or references if you are interested in the details.

Immudel-gp120 Regimen and Dosing

Since new T₄ cells are constantly being produced, we need not totally prevent their destruction, only reduce the rate at which they are being destroyed. The rate of B cell multiplication and replacement suggests that Immudel-gp120 could be taken once a month. This would be in the form of an intramuscular injection, to which would be added a small dose of Interleukin-2.

At first, the anti-gp120 antibody will attack the gp120 portion of Immudel-gp120, labeling it for destruction, and there will be large quantities of B cells which the drug will need to kill. Both of these factors will necessitate higher initial doses of Immudel-gp120, depending on the advancement of the disease. As B cells are killed and antibody levels decrease, the antibody competition with Immudel-gp120 and the quantity of target cells will decrease; therefore the required dose can correspondingly be reduced. Ultimately the person will need to stay on a low maintenance dose of the drug once a month for life. Since gp120 and B cells will always be produced, without Immudel-gp120 the cycle of antibody increase and corresponding T₄ cell shutdown could begin again.

Immudel-gp120 can easily be updated to remain maximally effective on various forms of gp120, including those present in both HIV I and HIV II. As HIV naturally mutates, different forms of gp120 become abundant. Although it is not necessary to use the exact forms of gp120 found in a patient for Immudel-gp120 to be effective, it is fairly trivial to modify the forms of gp120 used in the drug to increase and maintain full effectiveness.

Anticipated Side Effects in Humans

Although nothing can be guaranteed until tested in clinical trials, few side effects are anticipated for Immudel-gp120. Encouragingly, no side effects were observed when Immudel-gp120 was tested on human cells and in rats, as discussed in the next section, Pilot Test Results.

A survey of various existing immunotoxins reveals that, in general, the more narrow the target cell range the fewer side effects. Unlike Immudel-gp120, most existing immunotoxins employ an antibody targeting system which usually results in a greater target cell range and more non-specific effects. In contrast, Immudel-gp120 has a very narrow target cell range, which is promising.

• Brief Fever-Like Symptoms: A very similar drug is currently on the market for treatment of leukemia. This drug consists of the same receptorless diphtheria toxin attached to a different targeting molecule (a hormone to target T₄ cells). So far, the only side effects observed are fever-like symptoms (increased body temperature, sweating, aching joints, etc.) for an hour or so after injection. (115) We can anticipate similar reactions to Immudel-gp120, especially at higher doses.

• Reduced Immune Efficacy Unlikely: People have asked if it is possible that the small portion of B cells killed could happen to include all of those that respond to a particular disease or invader. For the following reasons, this is very unlikely. A single B cell responds to a specific small section (10 to 20 amino acids long) of a protein. Since most proteins contain many different such potential targets, it is unlikely that B cells for all such targets would be eliminated for any protein except gp120. Furthermore, the B cell/antibody arm of the immune system is most effective against bacteria and eukaryotic invaders, not viruses. (Viruses are best controlled by the T₈ arm of the immune system, which specifically destroys infected cells.) These organisms have many different surface proteins for the B cells and antibodies to target, so it is not necessary to rely on any one specific protein. Finally, even if it proves that Immudel-gp120 weakens the body's immune system to some particular invader, this is still a significant improvement over the complete collapse of the immune system seen in AIDS. (We would be happy to elaborate on the numerical probabilities involved if you Contact Us.)

• Diphtheria Toxin Cannot Revert: People have also inquired if the receptorless diphtheria toxin could regain its receptor, or could cause the disease diphtheria. The toxin has been made without ever having had a receptor. This is an omission of 146 amino acids, or over one quarter of the original protein (ref. 116, 117), so it could not spontaneously generate one. Additionally, the disease called diphtheria is caused by an infection with Corneybacterium diphtheriae bacteria and their constant high-level production of normal diphtheria toxin. Neither this bacterium nor its unmodified toxin is involved in any way.

  Domains of the Diptheria Toxin
  

  (Note: Routine diphtheria vaccinations cause antibody response to diphtheria toxin. However, this response is exclusively to the receptor portion of the complete diphtheria toxin. (126) Therefore, diphtheria vaccination will not cause an antibody attack on Immudel-gp120. Nor will our drug compromise the effects of diphtheria vaccination.)

• Antibody-Drug Complexes: Another question that is sometimes raised is the formation of antibody-drug complexes, since anti-gp120 antibody would bind to the gp120 portion of Immudel-gp120. Such complexes form naturally whenever antigen and antibody are present, and the body has mechanisms to eliminate them. In the case of AIDS, the drug-antibody complexing will be insignificant compared to the gp120-antibody complexing already occurring. Since anti-gp120 antibody will initially complex with Immudel-gp120, higher doses will be necessary at the beginning of treatment. Such complexing will be minimized after initial treatment reduces antibody titer.

• Bystander Macrophage Death: Macrophages roam the body and non-specifically internalize and destroy any foreign substance they encounter. One potential side effect is that macrophages which encounter and internalize Immudel-gp120 would also be poisoned. This bystander macrophage death would increase with increased doses. We expect this to be a very minor side effect, with an insignificant number of macrophages being killed. So far, for example, this has not been shown to be a problem with the new leukemia treatment. Likewise, both radiation and chemotherapy treatments do substantial damage to macrophages, yet the replacement rate for macrophages (a few days) is so fast that this damage is not considered a significant problem. Furthermore, if it were to become a significant problem, there is an antidote which would selectively protect macrophages from bystander death, while not impacting the efficacy of Immudel-gp120.

• Breakdown Pathway: Because Immudel-gp120 is a large protein drug it has a defined, well-characterized breakdown pathway. It will collect on the glomerular membrane in the kidney and be broken down by decay accelerating factor (CD55) without internalization by any cells. Unlike small molecule drugs, such as protease inhibitors, it should not be metabolized by the liver.

Summary Comparison of AIDS Drugs
	Existing Anti-Viral Drugs	Immudel-gp120
Function	Destroys HIV's ability to reproduce.	Destroys body's ability to make anti-gp120 antibodies.
Result	Fewer T4 cells destroyed by direct infection, indirect damage still done to immune system.	Fewer T4 cells destroyed indirectly by crosslinking and mislabeling, natural immune function able to keep HIV in remission.
Immune Reconstitution	Immune system fails to reconstitute even when viral load below detectable.	Immune system should reconstitute fully.
AIDS Wasting	Addressed only by other drugs.	Strong evidence for applicability.
AIDS Dementia	Not addressed.	Potential applicability.
Regimen	Multiple pills many times per day.	Monthly injection.
Side Effects	Hemolytic anemia, dangerous fat deposits (lipodystrophy like Cushing's Syndrome), diabetes, chronic nausea, etc.	At worst, fever like symptoms (sweating, aching joints, etc.) for about an hour after injection. [No other side effects predictable, but nothing is certain until it is tested in humans.]
Drug Resistance	Develops rapidly with even slight deviations from regimen. Resistant strains spreading.	Does not attack virus so resistance cannot be developed.

Immudel-gp120 has successfully undergone pilot tests for safety and efficacy. For these results, please see the next section, Pilot Test Results.

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