IP Library › Granted Patent US 10,323,090

Granted Patent B2

US 10,323,090 · App. 15/353,919 · Granted Jun 18, 2019

PD1 and/or LAG3 binders

Inventors: Edward Bowman (Redwood City, CA); Maribel Beaumont (San Mateo, CA); Marie-Ange Buyse (Merelbeke, BE); Carlo Boutton (Wielsbeke, BE); Bruno Dombrecht (Heusden, BE); David Vlerick (Gentbrugge, BE); Robert A. Kastelein (Portola Valley, CA)

Assignee: Merck Sharp & Dohme Corp.

C07K16/2803 A61K39/3955 A61K45/06 C07K16/18 C07K16/2818 C07K16/468 C07K2317/22 C07K2317/24 C07K2317/31 C07K2317/33 C07K2317/34 C07K2317/565 C07K2317/569 C07K2317/62 C07K2317/76 C07K2317/92

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Quick Facts

Patent No.: US 10,323,090
App. No.: 15/353,919
Granted: Jun 18, 2019
Kind: B2

External Links

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Abstract

The present invention provides molecules, such as ISVDs and Nanobodies, that bind to PD1 and LAG3 and, optionally to human serum albumin. These molecules have been engineered so as to reduce the incidence of binding by pre-existing antibodies in the bodies of a subject administered such a molecule. Methods for increasing immune response, treating cancer and/or treating an infectious disease with such molecules are provided.

Claims (280)

1. A multispecific binder comprising:

(a) an immunoglobulin single variable domain (ISVD) that binds to programed cell death protein 1 (PD1) comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 6; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 4 or SEQ ID NO: 7; and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 5; and

(b) an ISVD that binds to lymphocyte activation gene 3 (LAG3) comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 65 or SEQ ID NO: 154; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66 or SEQ ID NO: 139; and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 67.

2. The multispecific binder of claim 1 , wherein the ISVD that binds to PD1 comprises:

the amino acid sequence set forth in SEQ ID NO: 1 or 2 wherein the sequence comprises a mutation at residue 11 and/or 89; wherein said residue numbers are Kabat residue numbers.

3. The multispecific binder of claim 1 , wherein the ISVD that binds PD1 comprises the amino acid sequence

DVQLVESGGG VVQPGGSLRL SCAASGSIAS IHAMGWFRQA

PGKEREFVAV ITWSGGITYY ADSVKGRFTI SRDNSKNTVY

LQMNSLRPED TALYYCAGDK HQSSWYDYWG QGTLVTVSS

(SEQ ID NO: 57, or said sequence comprising a D1E mutation);

EVQLVESGGGLVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAV

ITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAIYYCAGDK

HQSSWYDYWGQGTLVTVSS

(SEQ ID NO: 98, or said sequence comprising a E1D mutation);

EVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAV

ITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDK

HQSSWYDYWGQGTLVTVSS

(SEQ ID NO: 99, or said sequence comprising a E1D mutation);

DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAV

ITVSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDK

HQSSFYDYWGQGTLVTVSS

(SEQ ID NO: 103, or said sequence comprising a D1E and/or N73S mutation);

DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAV

ITVSGGITYYADSVKGRFTISRDQSKNTVYLQMNSLRPEDTALYYCAGDK

HQSSFYDYWGQGTLVTVSS

(SEQ ID NO: 104, or said sequence comprising a D1E mutation);

DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAV

ITVSGGITYYADSVKGRFTISRDPSKNTVYLQMNSLRPEDTALYYCAGDK

HQSSFYDYWGQGTLVTVSS

(SEQ ID NO: 105, or said sequence comprising a D1E mutation),

DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAV

ITVSGGITYYADSVKGRFTISRDPSKNTVYLQMNSLRPEDTALYYCAGDK

HQSSFYDYWGQGTLVTVSS

(amino acids 1-119 of SEQ ID NO: 113 , or said sequence comprising a ME mutation);

DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAV

ITVSGGITYYADSVKGRFTISRDQSKNTVYLQMNSLRPEDTALYYCAGDK

HQSSFYDYWGQGTLVTVSS

(amino acids 1-119 of SEQ ID NO: 117, or said sequence comprising a D1E mutation);

DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAV

ITVSGGITYYADSVKGRFTISRDSSKNTVYLQMNSLRPEDTALYYCAGDK

HQSSFYDYWGQGTLVTVSS

(amino acids 1-119 of SEQ ID NO: 121, or said sequence comprising a D1E mutation).

4. The multispecific binder of claim 1 , wherein the ISVD that binds LAG3 comprises the amino acid sequence set forth in SEQ ID NO: 64.

5. The multispecific binder of claim 1 , wherein the multispecific binder further includes an ISVD that binds to human serum albumin comprising CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 60 or SEQ ID NO: 151; CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 61 or SEQ ID NO: 152; and CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 62.

6. A multispecific binder comprising:

(a) an immunoglobulin single variable domain (ISVD) that binds to programmed cell death protein 1 (PD1) comprising: a CDR1 comprising the amino acid sequence IHAMG (SEQ ID NO: 3) or GSIASIHAMG (SEQ ID NO: 6); a CDR2 comprising the amino acid sequence VITXSGGITYYADSVKG (SEQ ID NO: 4) or VITXSGGITY (SEQ ID NO: 7); and a CDR3 comprising the amino acid sequence DKHQSSXYDY (SEQ ID NO: 5);

(b) an immunoglobulin single variable domain that binds to lymphocyte activation gene 3 (LAG3) comprising: a CDR1 comprising the amino acid sequence GRTFSDYVMG (SEQ ID NO: 139) or DYVMG (amino acids 6-10 of SEQ ID NO: 65); a CDR2 comprising the amino acid sequence AISESGGRTHYADSVKG (SEQ ID NO: 66) or AISESGGRTH (SEQ ID NO: 66); and a CDR3 comprising the amino acid sequence TLLWWTSEYAPIKANDYDY (SEQ ID NO: 67); and,

7. The multispecific binder of claim 6 , wherein

(a) the immunoglobulin single variable domain that binds to PD1 comprises the amino acid sequence

(SEQ ID NO: 57)

DVQLVESGGG VVQPGGSLRL SCAASGSIAS IHAMGWFRQA

PGKEREFVAV ITWSGGITYY ADSVKGRFTI SRDNSKNTVY

LQMNSLRPED TALYYCAGDK HQSSWYDYWG QGTLVTVSS;

(SEQ ID NO: 98)

EVQLVESGGGLVQPGGSLRLSCAASGSIASIHAMGWERQAPGKEREFVAV

ITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAIYYCAGDK

HQSSWYDYWGQGTLVTVSS;

(SEQ ID NO: 99)

EVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWERQAPGKEREFVAV

ITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDK

HQSSWYDYWGQGTLVTVSS;

(amino acids 1-119 of SEQ ID NO: 101)

DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAV

ITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDK

HQSSWYDYWGQGTLVTVSS;

(amino acids 1-119 of SEQ ID NO: 101);

(SEQ ID NO: 103)

DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAV

ITVSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDK

HQSSFYDYWGQGTLVTVSS;

(SEQ ID NO: 104)

DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAV

ITVSGGITYYADSVKGRFTISRDQSKNTVYLQMNSLRPEDTALYYCAGDK

HQSSFYDYWGQGTLVTVSS;

(SEQ ID NO: 105)

DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAV

ITVSGGITYYADSVKGRFTISRDPSKNTVYLQMNSLRPEDTALYYCAGDK

HQSSFYDYWGQGTLVTVSS;

and,

(b) the immunoglobulin single variable domain that binds to LAG3 comprises the amino acid sequence

(SEQ ID NO: 64)

EVQLVE SGGGVVQPGG SLRLSCAASG RTFSDYVMGW FRQAPGKERE

FVAAISESGG RTHYADSVKG RFTISRDNSK NTLYLQMNSL

RPEDTALYYC ATTLLWWTSE YAPIKANDYD YWGQGTLVTV SS;

10 or

DVQLVESGGGVVQPGGSLRLSCAASGRTFSDYVMGWFRQAPGKEREFVAAISESGGRTHYADSVKGRFTISRDNSKNTLYLQMNSL RPEDTALYYCATTLLWWTSEYAPIKANDYDYWGQGTLVTVSS

(amino acids 1-128 of SEQ ID NO: 96).

8. The multispecific binder of claim 6 , wherein the C-terminal extender is an alanine.

9. The multispecific binder of claim 6 , wherein the multispecific binder comprises:

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 98;

a 35 GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 98;

a 35 GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 63;

a 35 GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 63;

a 35 GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a HSA ISVD comprising the amino acid sequence set forth in SEQ ID NO: 142; and

a C-terminal Alanine;

or,

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 57;

a 35 GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 99;

a 35 GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 35 GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 35 GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a HSA ISVD comprising the amino acid sequence set forth in SEQ ID NO: 142; and

a C-terminal Alanine;

or,

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 57;

a 20 GS linker comprising the amino acid sequence set forth in SEQ ID NO: 100;

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 99;

a 20 GS linker comprising the amino acid sequence set forth in SEQ ID NO: 100;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 20 GS linker comprising the amino acid sequence set forth in SEQ ID NO: 100;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 20 GS linker comprising the amino acid sequence set forth in SEQ ID NO: 100;

a HSA ISVD comprising the amino acid sequence set forth in SEQ ID NO: 142; and

a C-terminal Alanine;

or,

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 57;

a 9 GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 99;

a 9 GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 9 GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 9 GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a HSA ISVD comprising the amino acid sequence set forth in SEQ ID NO: 142; and

a C-terminal Alanine;

or,

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 57;

a 35GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 35GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a HSA ISVD comprising the amino acid sequence set forth in SEQ ID NO: 142; and

a C-terminal Alanine;

or,

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 57;

a 20GS linker comprising the amino acid sequence set forth in SEQ ID NO: 100;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 20GS linker comprising the amino acid sequence set forth in SEQ ID NO: 100;

a HSA ISVD comprising the amino acid sequence set forth in SEQ ID NO: 142; and

a C-terminal Alanine;

or,

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 57;

a 9GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 9GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a HSA ISVD comprising the amino acid sequence set forth in SEQ ID NO: 142; and

a C-terminal Alanine;

or,

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 105;

a 35GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 105 (wherein the Asp at position 1 is substituted with a Glu);

a 35GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 35GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a HSA ISVD comprising the amino acid sequence set forth in SEQ ID NO: 142; and

a C-terminal Alanine;

or,

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 105;

a 9GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 105 (wherein the Asp at position 1 is substituted with a Glu);

a 9GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 9GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a HSA ISVD comprising the amino acid sequence set forth in SEQ ID NO: 142; and

a C-terminal Alanine;

or,

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 105;

a 35GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 35GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a HSA ISVD comprising the amino acid sequence set forth in SEQ ID NO: 142; and

a C-terminal Alanine;

or,

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 105;

a 9GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 9GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a HSA ISVD comprising the amino acid sequence set forth in SEQ ID NO: 142; and

a C-terminal Alanine;

or,

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 104;

a 35GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 104 (wherein the Asp at position 1 is substituted with a Glu);

a 35GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 35GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a HSA ISVD comprising the amino acid sequence set forth in SEQ ID NO: 142; and

a C-terminal Alanine;

or,

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 104;

a 9GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 104 (wherein the Asp at position 1 is substituted with a Glu);

a 9GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 9GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a HSA ISVD comprising the amino acid sequence set forth in SEQ ID NO: 142; and

a C-terminal Alanine;

or,

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 104;

a 35GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 35GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a HSA ISVD comprising the amino acid sequence set forth in SEQ ID NO: 142; and

a C-terminal Alanine;

or,

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 104;

a 9GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 9GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a HSA ISVD comprising the amino acid sequence set forth in SEQ ID NO: 142; and

a C-terminal Alanine;

or,

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 103 (wherein the Asn at position 73 is substituted with Ser);

a 35GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO:103 (wherein the Asp at position 1 is substituted with Glu and the Asn at position 73 is replaced with Ser);

a 35GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 35GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a HSA ISVD comprising the amino acid sequence set forth in SEQ ID NO: 142; and

a C-terminal Alanine;

or,

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 103 (wherein the Asn at position 73 is substituted with Ser);

a 9GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO:103 (wherein the Asp at position 1 is substituted with Glu and the Asn at position 73 is substituted with Ser);

a 9GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 9GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a HSA ISVD comprising the amino acid sequence set forth in SEQ ID NO: 142; and

a C-terminal Alanine,

or,

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 103 (wherein the Asn at position 73 is substituted with Ser);

a 35 GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 35GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58;

a HSA ISVD comprising the amino acid sequence set forth in SEQ ID NO: 142; and

a C-terminal Alanine;

or,

a PD1 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 103 (wherein the Asn at position 73 is substituted with Ser);

a 9GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a LAG3 ISVD comprising the amino acid sequence set forth in SEQ ID NO: 64;

a 9 GS linker comprising the amino acid sequence set forth in SEQ ID NO: 125;

a HSA ISVD comprising the amino acid sequence set forth in SEQ ID NO: 142; and

a C-terminal Alanine; and,

wherein said residue numbers are Kabat residue numbers.

10. The multispecific binder of claim 6 , wherein the multispecific binder comprises the amino acid sequence set forth in SEQ ID NO: 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, or 124.

11. The multispecific binder of claim 6 , wherein the half-life extender is a human serum albumin ISVD that binds to human serum albumin comprising CDR1 comprising the amino acid sequence

GFTFSSFGMS (SEQ ID NO: 60) or SFGMS (SEQ ID NO: 151);

CDR2 comprising the amino acid sequence SISGSGSDTLYADSVKG (SEQ ID NO: 61) or SISGSGSDTL (SEQ ID NO: 152); and CDR3 comprising the amino acid sequence GGSLSR (SEQ ID NO: 62).

12. The multispecific binder of claim 11 , wherein the ISVD that binds human serum albumin comprises the amino acid sequence

(SEQ ID NO: 59)

EVQLVESGGG VVQPGNSLRL SCAASGFTFS SFGMSWVRQA

PGKGLEWVSS ISGSGSDTLYADSVKGRFTI SRDNAKTTLY

LQMNSLRPED TALYYCTIGG SLSRSSQGTL VTVSSA.

13. An injection device or vessel that comprises the multispecific binder of claim 6 .

14. A composition comprising a multispecific binder of claim 6 and at least one pharmaceutically acceptable carrier, diluent or excipient.

15. The composition of claim 14 , wherein the multispecific binder comprises the amino acid sequence set forth in SEQ ID NO: 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, or 124.

16. The composition of claim 15 , wherein the multispecific binder comprises the amino acid sequence set forth in SEQ ID NO:110.

17. A multispecific binder consisting of the amino acid sequence set forth in SEQ ID NO: 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, or 124.

18. A composition comprising the multispecific binder of claim 17 and at least one pharmaceutically acceptable carrier, diluent or excipient.

19. A multispecific binder consisting of the amino acid sequence set forth in SEQ ID NO: 110.

20. A composition comprising the multispecific binder of claim 19 and at least one pharmaceutically acceptable carrier, diluent or excipient.

21. A multispecific binder comprising a programmed cell death protein 1 (PD1) binder having the amino acid sequence set forth in SEQ ID NO: 57 and a lymphocyte activation gene 3 (LAG3) binder having the amino acid sequence set forth in SEQ ID NO: 64.

22. The multispecific binder of claim 21 , wherein the multispecific binder further comprises a human serum albumin (HSA) binder having the amino acid sequence set forth in SEQ ID NO: 142.

23. A multispecific binder comprising an N-terminal immunoglobulin single variable domain (ISVD) that binds programmed cell death protein 1 (PD1) comprising the amino acid sequence set forth in SEQ ID NO: 57; an ISVD that binds lymphocyte activation gene 3 (LAG3) comprising the amino acid sequence set forth in SEQ ID NO: 64; an ISVD that binds human serum albumin (HSA) comprising the amino acid sequence set forth in SEQ ID NO: 142; and a C-terminal Alanine.

24. A multispecific binder comprising an N-terminal immunoglobulin single variable domain (ISVD) that binds programmed cell death protein 1 (PD1) comprising the amino acid sequence set forth in SEQ ID NO: 57; a 35GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58; an ISVD that binds lymphocyte activation gene 3 (LAG3) comprising the amino acid sequence set forth in SEQ ID NO: 64; a 35GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58; an ISVD that binds human serum albumin (HSA) comprising the amino acid sequence set forth in SEQ ID NO: 142; and a C-terminal Alanine.

25. A composition comprising the multispecific binder of claim 21 and at least one pharmaceutically acceptable carrier, diluent or excipient.

26. A multispecific binder comprising the amino acid sequence set forth in SEQ ID NO: 110.

27. A composition comprising the multispecific binder of claim 26 and at least one pharmaceutically acceptable carrier, diluent or excipient.

28. A composition comprising the multispecific binder of claim 24 and at least one pharmaceutically acceptable carrier, diluent or excipient.

29. The injection device or vessel of claim 13 , wherein the multispecific binder is in association with a further therapeutic agent.

30. A composition comprising (a) a multispecific binder comprising an N- terminal immunoglobulin single variable domain (ISVD) that binds programmed cell death protein 1 (PD1) comprising the amino acid sequence set forth in SEQ ID NO: 57; an ISVD that binds lymphocyte activation gene 3 (LAG3) comprising the amino acid sequence set forth in SEQ ID NO: 64; an ISVD that binds human serum albumin (HSA) comprising the amino acid sequence set forth in SEQ ID NO: 142; and a C-terminal Alanine, and, (b) at least one pharmaceutically pharmaceutically acceptable carrier, diluent or excipient.

31. A composition comprising (a) a multispecific binder comprising an N-terminal immunoglobulin single variable domain (ISVD) that binds programmed cell death protein 1 (PD1) comprising the amino acid sequence set forth in SEQ ID NO: 57; a 35GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58; an ISVD that binds lymphocyte activation gene 3 (LAG3) comprising the amino acid sequence set forth in SEQ ID NO: 64; a 35GS linker comprising the amino acid sequence set forth in SEQ ID NO: 58; an ISVD that binds human serum albumin (HSA) comprising the amino acid sequence set forth in SEQ ID NO: 142; and a C-terminal Alanine, and, (b) at least one pharmaceutically pharmaceutically acceptable carrier, diluent or excipient.

Assignments (7)

MERGER Recorded Aug 8, 2022

From: MERCK SHARP & DOHME CORP.

To: MERCK SHARP & DOHME LLC

Reel/Frame 061102/0145 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 20, 2017

From: BOWMAN, EDWARD; BEAUMONT, MARIBEL; KASTELEIN, ROBERT A.

To: MERCK SHARP & DOHME CORP.

Reel/Frame 042076/0155 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 20, 2017

From: BUYSE, MARIE-ANGE; BOUTTON, CARLO; DOMBRECHT, BRUNO; VLERICK, DAVID

To: ABLYNX N.V.