MAB-problems

[Guest guest]

Dear Anupama,

You have explained nicely one of the draw back and its solution in case of MAB utility. Stated methods are in vitro of MAB production.

What is in vivo production of MAB?(not getting clear picture of this)

What are the advantages of one method over other?

Regards,

Dr Smita Mali

GMC, Nagpur.

From: anupama sukhlecha <anupama_acad@...>Subject: MAB-problemsnetrum Date: Friday, 7 March, 2008, 5:13 PM

Hi,

The problems with monoclonal therapy can be:

There so few monoclonals being used in human therapy a quarter century after their discovery. The main difficulty is that mouse antibodies are "seen" by the human immune system as foreign, and the human patient mounts an immune response against them, producing HAMA ("human anti-mouse antibodies") . These not only cause the therapeutic antibodies to be quickly eliminated from the host, but also form immune complexes that cause damage to the kidneys. (Monoclonal antibodies raised in humans would lessen the problem, but few people would want to be immunized in an attempt to make them and most of the attempts that have been made have been unsuccessful. )

Using genetic engineering it is possible to make mouse-human hybrid antibodies in an attempt to reduce the problem of HAMA.

Chimeric antibodies. The antibody combines the antigen-binding parts (variable regions) of the mouse antibody with the effector parts (constant regions) of a human antibody. Infliximab, rituximab, and abciximab are examples. Humanized antibodies. The antibody combines only the amino acids responsible for making the antigen binding site (the hypervariable regions) of a mouse (or rat) antibody with the rest of a human antibody molecule thus replacing its own hypervariable regions. Daclizumab, Vitaxin, Mylotarg®, Herceptin, and Xolair® are examples. In both cases, the new gene is expressed in mammalian cells grown in tissue culture (E. coli cannot add the sugars that are a necessary part of these glycoproteins). Looking ahead

Other ways of solving the problem of HAMA are being vigorously pursued. Transgenic mice. One of these is to exploit transgenic technology to make transgenic mice that:

have had human antibody gene loci inserted into their bodies (using the embryonic stem cell method). have had their own genes for making antibodies "knocked out". The result is a mouse that

can be immunized with the desired antigen produces human, not mouse, antibodies against the antigen can yield cells to be fused with myeloma cells to manufacture all-human monoclonal antibodies.

Phage display is another technique for making all-human monoclonal antibodies.

-Anupama

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[Guest guest]

Hello Anupama,

Yes definitely explaination clears the doubt. It is as per the terminology "In vivo" and "in vitro" production.

Does that mean only 'murine MAbs' are acquired by in vivo technique? Or other types of improved versions of MAbs like chimeric, humanised MAbs can also be produced in vivo?

Actually the concerned factor is how these hurdles can be overcome so that very positive attitude shown at the beginning of discussion by Dr Desai will be the reality.

Dr Smita Mali

GMC, Nagpur.

From: anupama sukhlecha <anupama_acad@ .co. in>Subject: MAB-problemsnetrumgroups (DOT) comDate: Friday, 7 March, 2008, 5:13 PM

Hi,

The problems with monoclonal therapy can be:

There so few monoclonals being used in human therapy a quarter century after their discovery. The main difficulty is that mouse antibodies are "seen" by the human immune system as foreign, and the human patient mounts an immune response against them, producing HAMA ("human anti-mouse antibodies") . These not only cause the therapeutic antibodies to be quickly eliminated from the host, but also form immune complexes that cause damage to the kidneys. (Monoclonal antibodies raised in humans would lessen the problem, but few people would want to be immunized in an attempt to make them and most of the attempts that have been made have been unsuccessful. )

Using genetic engineering it is possible to make mouse-human hybrid antibodies in an attempt to reduce the problem of HAMA.

Chimeric antibodies. The antibody combines the antigen-binding parts (variable regions) of the mouse antibody with the effector parts (constant regions) of a human antibody. Infliximab, rituximab, and abciximab are examples. Humanized antibodies. The antibody combines only the amino acids responsible for making the antigen binding site (the hypervariable regions) of a mouse (or rat) antibody with the rest of a human antibody molecule thus replacing its own hypervariable regions. Daclizumab, Vitaxin, Mylotarg®, Herceptin, and Xolair® are examples. In both cases, the new gene is expressed in mammalian cells grown in tissue culture (E. coli cannot add the sugars that are a necessary part of these glycoproteins). Looking ahead

Other ways of solving the problem of HAMA are being vigorously pursued. Transgenic mice. One of these is to exploit transgenic technology to make transgenic mice that:

have had human antibody gene loci inserted into their bodies (using the embryonic stem cell method). have had their own genes for making antibodies "knocked out". The result is a mouse that

can be immunized with the desired antigen produces human, not mouse, antibodies against the antigen can yield cells to be fused with myeloma cells to manufacture all-human monoclonal antibodies.

Phage display is another technique for making all-human monoclonal antibodies.

-Anupama

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