[RASMB] non-ideality in velocity [was: interference optics]

Arthur Rowe arthur.rowe at nottingham.ac.uk
Tue Apr 8 08:24:01 PDT 2008


Hi Allen

Good point, especially with regard to antibodies.

However, I fear that the wide world of bio/pharma has yet to come to terms
with the need for both reversible and irreversible aggregation to be
characterised as universal practice.

Regards

Arthur


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Arthur J Rowe
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University of Nottingham
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Hello Borries -

At 11:21 AM 4/8/2008, you wrote:

>So my question is: Why are drug companies interested in the reversible
>kind, or is there another reason to measure at high concentration?

1. Reversible self-association causes large increases in viscosity
(see recent work of Steve Shire and coworkers), which in turn causes
problems in administration of concentrated immunoglobulin via
injection through narrow bore needles.  Different monoclonal
antibodies have significantly different tendencies to reversibly
self-associate at high concentration.  Thus screening of candidate
engineered antibodies for tendency to reversibly self-associate at
high concentration is an essential part of the drug development process.

2. Directly following administration there exists a bolus of locally
highly concentrated antibody at the site of administration which
requires time to dissipate.  Reversibly formed aggregates therefore
exist with a significant lifetime.  The physiological effects of such
aggregates are unknown, but it is possible that some oligomeric
species may be mistakenly identified as foreign proteins and
therefore break immune tolerance.

For both of these reasons the FDA wants pharmaceutical companies to
characterize formulations of monoclonal antibodies with respect to
both reversible and irreversible self-association.   The former
requires measurement at high concentration.

Allen 

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