Bifunctional molecules containing IL-7 variants

JP7872226B2Active Publication Date: 2026-06-09OSE IMMUNOTHERAPEUTICS SA
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Patent Information

Authority / Receiving Office
JP · JP
Patent Type
Patents
Current Assignee / Owner
OSE IMMUNOTHERAPEUTICS SA
Filing Date
2020-12-17
Publication Date
2026-06-09

AI Technical Summary

Benefits of technology

【0007】 本発明者らは、二機能性分子の分布及び排除を向上させてin vivoでの生物学的効果を増強するために、IL-7の変異及び最適化されたFc骨格を提供する。本発明者らは、IL-7の変異体が、特にIgGアイソタイプ及びリンカー長と組み合わせると、二機能性分子のより良好な分布及びより長いin vivo半減期を可能することを観察した。

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Abstract

The present invention relates to IL-7 variants, bifunctional molecules containing same, and uses thereof.
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Claims

1. A bifunctional molecule containing an interleukin-7 (IL-7) variant conjugated to the binding portion, - The binding portion includes an antibody or antibody fragment containing an antigen-binding domain that binds to PD-1, - The IL-7 variant exhibits at least 90% identity with wild-type human IL-7 (wth-IL-7), comprising or consisting of the amino acid sequence shown in Sequence ID No. 1, and the variant includes the W142H or W142Y amino acid mutation, with the amino acid numbering as shown in Sequence ID No. 1, making it a bifunctional molecule.

2. The molecule according to claim 1, wherein the amino acid mutation i) reduces the affinity of the IL-7 variant to the IL-7 receptor (IL-7R) compared to the affinity of wth-IL-7 to IL-7R, and ii) improves the pharmacokinetics of the bifunctional molecule containing the IL-7 variant compared to the bifunctional molecule containing wth-IL-7.

3. The molecule according to claim 1, wherein the IL-7 variant comprises the amino acid substitution of W142H.

4. The molecule according to claim 1, wherein the IL-7 variant comprises the W142Y amino acid substitution.

5. The molecule according to claim 1, wherein the IL-7 variant comprises the amino acid sequence of SEQ ID NO:

5.

6. The molecule according to claim 1, wherein the IL-7 variant comprises the amino acid sequence of SEQ ID NO:

6.

7. The aforementioned anti-PD-1 antibodies or antibody fragments include pembrolizumab, nivolumab, pizilizumab, semiprimab, camrelizumab, AUNP12, AMP-224, AGEN-2034, tisreizumab, spartalizumab, MK-3477, SCH-900475, PF-06801591, JNJ-63723283, gonolimuzumab, LZM-009, BCD-100, SHR-1201, BAT-1306, AK-103, MEDI-0680, MEDI0608, and JS001 (Si-Yang Liu et al., J. Hematol.). (as described in Oncol. Vol. 10: p. 136 (2017)), BI-754091, CBT-501, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110 (as described in International Publication No. 2014 / 194302), AGEN2034 (as described in International Publication No. 2017 / 040790), MGA012 (as described in International Publication No. 2017 / 19846), IBI308 (as described in International Publication No. 2017 / 024465, International Publication No. 2017 / 025016, International Publication No. 2017 / 132825, The molecule according to claim 1, comprising an antigen-binding domain of an anti-PD-1 antibody selected from the group consisting of RG7769 (Roche), XmAb20717, MEDI5752, FS118, SL-279252, and XmAb23104 (as described in International Publication No. 2017 / 133540), or comprising a Fab or scFv domain derived from any of these antibodies.

8. The molecule according to any one of claims 1 to 7, wherein the IL-7 variant further comprises a group of amino acid substitutions selected from the group consisting of C2S-C141S and C47S-C92S, C2S-C141S and C34S-C129S, and C47S-C92S and C34S-C129S, and the amino acid numbering is as shown in SEQ ID NO:

1.

9. The molecule according to any one of claims 1 to 7, wherein the IL-7 variant further comprises an amino acid substitution selected from the group consisting of D74E, D74Q, and D74N, and the amino acid numbering is as shown in Sequence ID No.

1.

10. The molecule according to any one of claims 1 to 7, wherein the IL-7 variant comprises the amino acid sequence shown in SEQ ID NO: 5 or 6.

11. The molecule according to any one of claims 1 to 7, wherein the binding portion includes a heavy chain constant domain.

12. The molecule according to claim 11, wherein the binding portion comprises the heavy chain constant domain of human IgG1.

13. The bonding portion is T250Q / M428L;M252Y / S254T / T256E+H433K / N434F;E233P / L234V / L235A / G236A+A327G / A330S / P331S;E333A;S239D / A330L / I332E;P257I / Q311;K326W / E333S;S239D / I332E / G236A;N297A;L234A / The molecule according to claim 11, comprising a heavy chain constant domain of human IgG1, which is selected from the group consisting of L235A;N297A+M252Y / S254T / T256E;K322A; and K444A, or a substitution or combination of substitutions selected from the group consisting of N297A alone or N297A in combination with M252Y / S254T / T256E, and L234A / L235A.

14. The molecule according to any one of claims 1 to 7, wherein the binding portion includes the heavy chain constant domain of human IgG4.

15. The molecule according to claim 14, wherein the binding portion comprises a heavy chain constant domain of human IgG4, the binding portion comprising a substitution or combination of substitutions selected from the group consisting of S228P, L234A / L235A, S228P+M252Y / S254T / T256E, and K444A.

16. The molecule according to any one of claims 1 to 7, wherein the N-terminus of the IL-7 variant is directly fused to the C-terminus of the heavy chain constant domain or light chain constant domain of the PD-1-binding antibody or antibody fragment, or is indirectly fused to the C-terminus of the heavy chain constant domain or light chain constant domain of the PD-1-binding antibody or antibody fragment via a peptide linker.

17. The molecule according to claim 16, wherein the N-terminus of the IL-7 variant is directly fused to the C-terminus of the heavy chain constant domain of the PD-1 binding antibody or antibody fragment, or is indirectly fused to the C-terminus of the heavy chain constant domain of the PD-1 binding antibody or antibody fragment via a peptide linker.

18. The IL-7 variant is selected from the group consisting of GGGGS (SEQ ID NO: 68), GGGGSGGGS (SEQ ID NO: 67), GGGGSGGGGS (SEQ ID NO: 69), and GGGGSGGGGSGGGGS (SEQ ID NO: 70), or (GGGGS) 3 The molecule according to claim 16, wherein the molecule is fused to the PD-1 binding antibody or antibody fragment by a peptide linker.

19. The molecule according to any one of claims 1 to 7, wherein the PD-1-binding antigen-binding domain is a Fab domain, Fab', a single-chain variable fragment (scFV), or a single-domain antibody (sdAb).

20. An isolated nucleic acid molecule or a group of isolated nucleic acid molecules encoding a bifunctional molecule as described in any one of claims 1 to 7.

21. A host cell containing an isolated nucleic acid molecule as described in claim 20.

22. A pharmaceutical composition comprising a bifunctional molecule according to any one of claims 1 to 7, a nucleic acid molecule according to claim 20, or a host cell according to claim 21.

23. A molecule according to any one of claims 1 to 7, a nucleic acid molecule according to claim 20, a host cell according to claim 21, or a pharmaceutical composition according to claim 22, for use as a pharmaceutical.

24. A molecule according to any one of claims 1 to 7, a nucleic acid molecule according to claim 20, a host cell according to claim 21, or a pharmaceutical composition according to claim 22, for use as a pharmaceutical for the treatment of cancer or infectious disease.