I have heard about human anti-mouse antibodies (HAMAs) and read that HAMAs neutralize murine antibodies, therefore decreasing the effectiveness of those murine antibodies. Is this true that HAMAs neutralize the murine antibodies? How?
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1$\begingroup$ @user137 please don't answer questions in comments. Write a full answer instead. $\endgroup$– MattDMoDec 2, 2014 at 19:29
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$\begingroup$ @MattDMo It's fixed, just took me a while to get the protein sequences aligned. I don't like to make answers without some evidence. $\endgroup$– user137Dec 2, 2014 at 20:04
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1$\begingroup$ @MattDMo - I'm curious, this is second comment regarding answering in comments I've seen today. I wasn't aware this is normal policy. Personally I often leave a brief answer in a comment if I don't have time (or patients) to write a full good quality answer - I just put the comment in, if someone wants to take it for an answer thats fine by me. Perhaps there needs to be a meta post to discuss policy? (I don't know the extent of the answer that was left as a comment here, but certainly on the other I saw a user was told to put a quick one line comment in to a proper answer) $\endgroup$– rg255Dec 2, 2014 at 22:09
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$\begingroup$ @GriffinEvo see this meta post for a previous discussion on the phenomenon, and of course this recent related post as well. Regarding the (now-deleted) answer-as-comment here, it was probably 6 or 7 lines long, and covered all the points in the answer below, with the exception of the alignment. $\endgroup$– MattDMoDec 2, 2014 at 22:27
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2 Answers
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It's common for the human immune system to create antibodies against many proteins, even some human proteins. Hemophiliacs who receive regular doses of clotting factor proteins often develop neutralizing antibodies against the clotting factor proteins, even though they are a human protein1.
Therefore it's not surprising that antibodies would be developed against mouse antibodies. There are differences between mouse and human antibodies, and human antibodies may bind to these different regions. I found the amino acid sequences for human2 and mouse3 immunoglobulin gamma heavy chain constant region and aligned them by hand and marked the matching amino acids:
Human: MELGLSWVFLVAILEGVQCEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARECDNWF DPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
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Mouse: MDSRLNLVFLVLILKGVQCEVQLVESGGGLVKPGGSRKLSCAASGFTFSDYGMHWVRQAPEKGLEWVAYINSGSTTIYYADTVKGRFTISRDNAKNTLFLQMTSLRSEDTAMYYCARELWLRRIDYWGQGTTITVSSAKTTPPSVYPLAPGCGDTTGSSVTLGCLVKGYFPESVTVTWNSGSLSSSVHTFPALLQS GLYTMSSSVTVPSSTWPSQTVTCSVAHPASSTTVDKKLEPSGPISTINPCPPCKECHKCPAPNLEGGPSVFIFPPNIKDVLMISLTPKVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTIRVVSALPIQHQDWMSGKEFKCKVNNKDLPSPIERTISKIKGLVRAPQVYILPPPAEQLSRKDVSLTCLVVGFNPGDISVEWTSNGHTEENYKDTAPVLDSDGSYFIYSKLDIKTSKWEKTDSFSCNVRHEGLKNYYLKKTISRSPGK
As you can see, there are a lot of matching residues, but several differences. Keep in mind that antibodies also contain light chains, and that there are several other types of antibodies, I just used the IgG heavy chain as an example.
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$\begingroup$ is there a way to prevent this? Also, how does this neutralize the antibodies? $\endgroup$– TanMathDec 2, 2014 at 20:06
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$\begingroup$ This could be prevented by using human antibody genes in cell culture instead of growing antibodies in mice and extracting them from the blood. As far as neutralization goes, the human antibody may just mark it for uptake by white blood cells. $\endgroup$– user137Dec 2, 2014 at 20:14
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$\begingroup$ user137's comment about opsonized particles being marked for phagocytosis by macrophages is right on. There are a number of ways that antibodies can be neutralized (e.g. steric hinderance), but being eaten up definitely does the trick. However, growing antibodies in culture won't solve the problem. They are recognized, in large part, just by their Amino Acid sequence, rather than any culture conditions (you might make an argument for glycosylation). The variability of antibodies will always make them vulnerable to immune responses. There are even HAHA (human anti-human antibody responses. $\endgroup$ Aug 14, 2015 at 13:36
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As mentioned in the comment, all antibodies have constant regions and variable regions. The variable regions are the binding sites on the ends of the two arms, and the constant regions are the rest of the molecule. When humans are injected with murine antibodies, the immune system recognises and sets up an immune response to them, through generation of HAMA. This affects the efficacy of the antibody because it is attacked the same way a pathogenic substance would be. Antibodies have different effects, but the most important one in this instance is through opsonisation (http://en.wikipedia.org/wiki/Opsonin#Examples). Because antibodies have two arms, they can bind multiple targets and cause a grouping and clumping. This also causes activation and phagocytosis through phagocytes (generally macrophages) which will ingest and destroy the therapeutic antibodies.
Antibodies that are mostly human with just mouse variable regions have been created to try and counter this problem, known as chimeric antibodies. Humanised antibodies are also available, which are entirely human with only the very tips of the variable regions (known as the hypervariable regions) are from mice. This reduces the problem as far as possible (http://en.wikipedia.org/wiki/Fusion_protein#Chimeric_protein_drugs).
