DK2307455T3 - Opløselighedsoptimering for immunbindere - Google Patents
Opløselighedsoptimering for immunbindere Download PDFInfo
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- DK2307455T3 DK2307455T3 DK09768694.3T DK09768694T DK2307455T3 DK 2307455 T3 DK2307455 T3 DK 2307455T3 DK 09768694 T DK09768694 T DK 09768694T DK 2307455 T3 DK2307455 T3 DK 2307455T3
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
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Claims (14)
1. Immunbinder omfattende ét af følgende opløselighedsfremmende motiver i tung kæde aminosyrepositionerne 12, 103 og 144 (AHo nummereringen): (a) serin (S) ved tung kæde aminosyreposition 12; (b) serin (S) ved tung kæde aminosyreposition 103; og (c) threonin (T) ved tung kæde aminosyreposition 144; eller (a1) serin (S) ved tung kæde aminosyreposition 12; (b1) threonin (T) ved tung kæde aminosyreposition 103; og (c1) serin (S) ved tung kæde aminosyreposition 144; eller (a2) serin (S) ved tung kæde aminosyreposition 12; (b2) threonin (T) ved tung kæde aminosyreposition 103; og (c2) threonin (T) ved tung kæde aminosyreposition 144.
2. Immunbinder ifølge krav 1, som yderligere omfatter (a) aspartansyre (D) ved let kæde aminosyreposition 31; (b) glutaminsyre (E) ved let kæde aminosyreposition 83; (c) arginin (R) ved tung kæde aminosyreposition 43; (d) leucin (L) ved tung kæde aminosyreposition 67; og/eller (e) alanin (A) ved tung kæde aminosyreposition 78.
3. Fremgangsmåde til at fremme opløseligheden for en immunbinder, hvilken immunbinder omfatter en tung kæde variabel region (Vh), eller et fragment deraf, hvilken fremgangsmåde omfatter: A) udvælgelse af i det mindste tre aminosyrepositioner i VH-regionen for mutation; og B) mutering af de i det mindste tre aminosyrepositioner, som er valgt til mutation, hvor de i det mindste tre aminosyrepositioner er tung kæde aminosyrepositionerne 12, 103 og 144 (i overensstemmelse med AHo nummereringskonventionen) og mute-ringen omfatter erstatning af aminosyrerne ved de valgte aminosyrepositioner med en hydrofil aminosyre.
4. Fremgangsmåde ifølge krav 3, hvor den hydrofile aminosyre er (a) serin (S) ved tung kæde aminosyreposition 12; (b) serin (S) eller threonin (T) ved tung kæde aminosyreposition 103; og/eller (c) serin (S) eller threonin (T) ved tung kæde aminosyreposition 144.
5. Fremgangsmåde ifølge krav 3 eller 4, hvor aminosyren ved aminosyrepositionen, som er valgt til mutation, er en hydrofob aminosyre.
6. Fremgangsmåde ifølge krav 5, hvor den hydrofobe aminosyre er leucin (L) eller valin (V).
7. Fremgangsmåde ifølge ethvert af kravene 3 til 6, hvor den valgte aminosyre til mutation af (a) aminosyren ved tung kæde aminosyreposition 12 er valin (V); (b) aminosyren ved tung kæde aminosyreposition 103 er valin (V); og (c) aminosyren ved tung kæde aminosyreposition 144 er leucin (L).
8. Fremgangsmåde ifølge ethvert af kravene 3 til 7, hvor den termiske stabilitet, tilbageforing, ekspressionsudbytte, aggregation og/eller bindingsaktivitet for immunbinderen ikke påvirkes negativt ved mutationen.
9. Fremgangsmåde ifølge ethvert af kravene 3 til 8, hvor mutationen resulterer i det mindste i en to ganges forøgelse i opløselighed.
10. Fremgangsmåde ifølge ethvert af kravene 3 til 9, hvor mutationen yderligere omfatter trinnet med at indføre én eller flere mutationer ved en aminosyreposition (AHo nummereringskonventionen) valgt fra gruppen bestående af: (a) aspartansyre (D) ved let kæde aminosyreposition 31; (b) glutaminsyre (E) ved let kæde aminosyreposition 83; (c) arginin (R) ved tung kæde aminosyreposition 43; (d) leucin (L) ved tung kæde aminosyreposition 67; og (e) alanin (A) ved tung kæde aminosyreposition 78.
11. Immunbinder fremstillet i overensstemmelse med fremgangsmåden ifølge ethvert af kravene 3 til 10.
12. Immunbinder ifølge ethvert af kravene 1,2 eller 11, som er et scFv-antistof, et fuld-længde-immunoglobulin, et Fab-fragment, et Dab eller et nanolegeme.
13. Immunbinder ifølge ethvert af kravene 1,2, 11 eller 12, hvor immunbinderen specifikt binder til humant TNFa eller til humant VEGF.
14. Sammensætning omfattende immunbinder ifølge ethvert af kravene 1,2, 11, 12 eller 13, og et farmaceutisk acceptabelt bærestof.
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