Igg fc variants for veterinary use
A variant, IgG-dfc technology, applied in the direction of veterinary vaccines, antibodies, antibody mimics/scaffolds, etc., can solve problems such as weak CD16, no protein A binding properties, and weak C1q
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[0431] The pharmaceutical composition can be stored in lyophilized form. Thus, in some embodiments, the method of preparation includes a lyophilization step. The lyophilized composition can then be reconstituted, usually as an aqueous composition suitable for parenteral administration, prior to administration to dogs, cats or horses. In other embodiments, particularly when the variant IgG Fc polypeptides or other polypeptides described herein are highly stable to thermal and oxidative denaturation, the pharmaceutical composition may be stored as a liquid, i.e. as an aqueous composition, It can be administered directly or in appropriate dilutions to dogs, cats or horses. Lyophilized compositions can be reconstituted with sterile water for injection (WFI). Bacteriostatic agents such as benzyl alcohol may be included. Accordingly, the present invention provides pharmaceutical compositions in solid or liquid form.
[0432] When administered, the pH of the pharmaceutical compos...
Embodiment 1
[0446] For increased protein A binding
[0447] and / or reduced complement fixation and / or reduced CD16 binding variant canine IgG Fc polypeptides
[0448] Affinity purification of antibodies using protein A is a well-established process. However, of the four subtypes of canine IgG, only IgG-B Fc (eg, SEQ ID NO:2 or SEQ ID NO:3) has protein A binding affinity. Canine IgG-A Fc (eg, SEQ ID NO:1), IgG-C Fc (eg, SEQ ID NO:4 or SEQ ID NO:5) and IgG-D Fc (eg, SEQ ID NO:6) have weak with or without measurable protein A binding affinity. Variant canine IgG-A Fc, IgG-C Fc and IgG-D Fc polypeptides were designed for altered Protein A binding.
[0449] Furthermore, canine IgG-B Fc and IgG-C Fc have complement activity and bind to C1q, whereas canine IgG-A Fc and IgG-D Fc have weak or no measurable binding affinity to C1q. Variant canine IgG-B Fc and IgG-C Fc polypeptides were designed to potentially reduce CIq binding and / or potentially reduce complement-mediated immune responses.
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Embodiment 2
[0472] Variant canine IgG-A and IgG-D Fc polypeptides with increased protein A binding and / or increased complement fixation and / or increased CD16 binding
[0473] Based on the amino acid positions identified as being involved in the binding of Protein A, C1q and CD16 as described in Example 1, in order to potentially increase the binding of Protein A, C1q and / or CD16 to canine IgG-A Fc and IgG-DFc, a Gain-of-function canine IgG-A Fc and IgG-D Fc polypeptides were obtained. For example, variant canine IgG-A and IgG-D Fc polypeptides can be designed with one or more amino acid substitutions in the Protein A binding region, C1q binding region, and / or CD16 binding region to correspond to binding proteins A, C1q and and / or the sequence of the wild-type canine IgG Fc polypeptide of CD16.
[0474] Single, double or triple variant canine IgG-A and / or IgG-D polypeptides can be prepared by combining one or more of the amino acid substitutions listed in Table 6. For example, variants o...
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