Large immune complexes are formed when a patient with paroxysmal nocturnal hemoglobinuria (PNH) is simultaneously exposed to 2 anticomplement component 5 (C5) antibodies, such as eculizumab and investigational drugs crovalimab and pozelimab, according to a study published in PLOS One.
To analyze the formation of multivalent complexes in vitro, the researchers performed size exclusion chromatography and multiangle light scattering. They used recombinant anti-C5 monoclonal antibodies TPP-2799 and TPP-3544, which have the same sequences as crovalimab and pozelimab.
According to the results, each of the 2 antibodies bound C5 noncompetitively with eculizumab. In phosphate-buffered saline, the complex of C5 and eculizumab measured less than 500 kDa. When other antibodies were added at levels ranging from equimolar up to a fivefold excess over eculizumab and C5, various complexes measuring more than 1500 kDa were detected.
The formation of multivalent complexes was also observed by size exclusion chromatography monitored by fluorescence detection when fluorescently labeled eculizumab and either of the other two antibodies were incorporated into human plasma.
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“The present findings raise potentially important general considerations prior to converting a patient from one IgG monoclonal antibody to a second antibody to the same target. This is particularly important as the available number of IgG-based antibodies against a given target increases,” Cone and colleagues explained.
“Before contemplating a switch from one antibody to another it is advised to consider: 1) whether the conversion features antibodies that are non-competing; 2) the degree to which the first antibody can be eliminated from the patient circulation prior to administration of the second antibody; 3) the latitude for selection of a dose of the second antibody that will disfavor the formation of large complexes and which in turn is a function of the therapeutic target level.”
Eculizumab binds the MG7 domain, whereas crovalimab and pozelimab interact with the MG1 domain and MG6 domain, respectively. When patients are converted from one antibody to another, it is sometimes necessary to maintain complete pharmacodynamic suppression to avoid even low levels of free C5 that could result in an intravascular hemolytic crisis.
The researchers also pointed out the need to characterize the pharmacodynamic and pharmacokinetic properties of these complexes in detail to prevent their formation.
Reference
Cone J, Kimmel L, Zhang Y, Johnson K, Sheridan D, Tamburini P. Characterization of multivalent complexes formed in the presence of more than one conventional antibody to terminal complement component C5. PLoS One. Published online April 20, 2023. doi:10.1371/journal.pone.0284502
