Therapeutic molecules that bind to LAG3 and PD1

An isolated binding agent comprising a first (VH) single domain antibody that binds to human LAG-3 and a second (VH) single domain antibody that binds to human LAG-3, wherein the first and/or second (VH) single domain antibody that binds to human LAG-3 comprises a CDR1 sequence as shown in SEQ ID NO:

• 1 or a CDR1 sequence as shown in SEQ ID NO:
• 1 comprising a Y to F substitution in CDR1 at position 32 of the sequence as shown in SEQ ID NO:
• 4, a CDR2 sequence as shown in SEQ ID NO:
• 2 or a CDR2 sequence as shown in SEQ ID NO:
• 2 comprising a N to S substitution in CDR2 at position 57 of the sequence as shown in SEQ ID NO:
• 4, a S to T substitution in CDR2 at position 58 of the sequence as shown in SEQ ID NO:
• 4, a N to I substitution in CDR2 at position 54 of the sequence as shown in SEQ ID NO:
• 4, a G to S substitution in CDR2 at position 55 of the sequence as shown in SEQ ID NO:
• 4, a G to D substitution in CDR2 at position 56 of the sequence as shown in SEQ ID NO:
• 4, a N to I substitution in CDR2 at position 57 of the sequence as shown in SEQ ID NO:
• 4, or a G to A substitution in CDR2 at position 59 of the sequence as shown in SEQ ID NO:
• 4, and a CDR3 sequence as shown from SEQ ID NO:
• 3 or a CDR3 sequence as shown in SEQ ID NO:
• 3 comprising a S to V substitution in CDR3 at position 106 of the sequence as shown in SEQ ID NO:
• 4, a S to A substitution in CDR3 at position 108 of the sequence as shown in SEQ ID NO:
• 4, or a A to T substitution in CDR3 at position 107 of the sequence as shown in SEQ ID NO:
• 4, or a CDR1 sequence as shown in SEQ ID NO:
• 5, a CDR2 sequence as shown in SEQ ID NO:
• 6, and a CDR3 sequence as shown in SEQ ID NO:
• 7.

An isolated human heavy chain variable domain (VH) single domain antibody that binds to human LAG-3 comprising a CDR1 sequence as shown in SEQ ID NO:

• 1, a CDR2 sequence as shown in SEQ ID NO:
• 2 comprising a N to S substitution in CDR2 at position 57 of the sequence as shown in SEQ ID NO:
• 4 and a S to T substitution in CDR2 at position 58 of the sequence as shown in SEQ ID NO:
• 4, and a CDR3 sequence as shown in SEQ ID NO:
• 3,_or a CDR1 sequence as shown in SEQ ID NO:
• 1, a CDR2 sequence as shown in SEQ ID NO:
• 2 comprising a N to I substitution in CDR2 at position 54 of the sequence as shown in SEQ ID NO:
• 4, and a CDR3 sequence as shown in SEQ ID NO:
• 3, or a CDR1 sequence as shown in SEQ ID NO:
• 1 comprising a Y to F substitution in CDR1 at position 32 of the sequence as shown in SEQ ID NO:
• 4, a CDR2 sequence as shown in SEQ ID NO:
• 2 comprising a S to T substitution in CDR2 at position 58 of the sequence as shown in SEQ ID NO:
• 4, and a CDR3 sequence as shown in SEQ ID NO:
• 3, or a CDR1 sequence as shown in SEQ ID NO:
• 1 comprising a Y to F substitution in CDR1 at position 32 of the sequence as shown in SEQ ID NO:
• 4, a CDR2 sequence as shown in SEQ ID NO:
• 2 comprising a G to S substitution in CDR2 at position 55 of the sequence as shown in SEQ ID NO:
• 4, a G to D substitution in CDR2 at position 56 of the sequence as shown in SEQ ID NO:
• 4, a N to I substitution in CDR2 at position 57 of the sequence as shown in SEQ ID NO:
• 4, a S to T substitution in CDR2 at position 58 of the sequence as shown in SEQ ID NO:
• 4, and a G to A substitution in CDR2 at position 59 of the sequence as shown in SEQ ID NO:
• 4, and a CDR3 sequence as shown in SEQ ID NO:
• 3, or a CDR1 sequence as shown in SEQ ID NO:
• 1 comprising a Y to F substitution in CDR1 at position 32 of the sequence as shown in SEQ ID NO:
• 4, a CDR2 sequence as shown in SEQ ID NO:
• 2 comprising a S to T substitution in CDR2 at position 58 of the sequence as shown in SEQ ID NO:
• 4, and a CDR3 sequence as shown in SEQ ID NO:
• 3 comprising a S to V substitution in CDR3 at position 106 of the sequence as shown in SEQ ID NO:
• 4 and a S to A substitution in CDR3 at position 108 of the sequence as shown in SEQ ID NO:
• 4, or a CDR1 sequence as shown in SEQ ID NO:
• 1, a CDR2 sequence as shown in SEQ ID NO:
• 2, and a CDR3 sequence as shown in SEQ ID NO:
• 3 comprising a A to T substitution in CDR3 at position 107 of the sequence as shown in SEQ ID NO:
• 4, or a CDR1 sequence as shown in SEQ ID NO:
• 1, a CDR2 sequence as shown in SEQ ID NO:
• 2 comprising a G to D substitution in CDR2 at position 56 of the sequence as shown in SEQ ID NO:
• 4, a N to S substitution in CDR2 at position 57 of the sequence as shown in SEQ ID NO:
• 4, and a S to T substitution in CDR2 at position 58 of the sequence as shown in SEQ ID NO:
• 4, and a CDR3 sequence as shown in SEQ ID NO:
• 3.

An isolated binding agent comprising a first (VH) single domain antibody that binds to human LAG-3 and a second (VH) single domain antibody that binds to human LAG-3, wherein the first and/or second (VH) single domain antibody that binds to human LAG-3 comprises a CDR1 sequence as shown in SEQ ID NO:

• 1, a CDR2 sequence as shown in SEQ ID NO:
• 2 comprising a N to S substitution in CDR2 at position 57 of the sequence as shown in SEQ ID NO:
• 4 and a S to T substitution in CDR2 at position 58 of the sequence as shown in SEQ ID NO:
• 4, and a CDR3 sequence as shown in SEQ ID NO:
• 3, or a CDR1 sequence as shown in SEQ ID NO:
• 1, a CDR2 sequence as shown in SEQ ID NO:
• 2 comprising a N to I substitution in CDR2 at position 54 of the sequence as shown in SEQ ID NO:
• 4, and a CDR3 sequence as shown in SEQ ID NO:
• 3, or a CDR1 sequence as shown in SEQ ID NO:
• 1 comprising a Y to F substitution in CDR1 at position 32 of the sequence as shown in SEO ID NO:
• 4, a CDR2 sequence as shown in SEQ ID NO:
• 2 comprising a S to T substitution in CDR2 at position 58 of the sequence as shown in SEQ ID NO:
• 4, and a CDR3 sequence as shown in SEQ ID NO:
• 3, or a CDR1 sequence as shown in SEQ ID NO:
• 1 comprising a Y to F substitution in CDR1 at position 32 of the sequence as shown in SEQ ID NO:
• 4, a CDR2 sequence as shown in SEQ ID NO:
• 2 comprising a G to S substitution in CDR2 at position 55 of the sequence as shown in SEQ ID NO:
• 4, a G to D substitution in CDR2 at position 56 of the sequence as shown in SEQ ID NO:
• 4, a N to I substitution in CDR2 at position 57 of the sequence as shown in SEQ ID NO:
• 4, a S to T substitution in CDR2 at position 58 of the sequence as shown in SEQ ID NO:
• 4, and a G to A substitution in CDR2 at position 59 of the sequence as shown in SEQ ID NO:
• 4, and a CDR3 sequence as shown in SEQ ID NO:
• 3, or a CDR1 sequence as shown in SEQ ID NO:
• 1 comprising a Y to F substitution in CDR1 at position 32 of the sequence as shown in SEQ ID NO:
• 4, a CDR2 sequence as shown in SEQ ID NO:
• 2 comprising a S to T substitution in CDR2 at position 58 of the sequence as shown in SEQ ID NO:
• 4, and a CDR3 sequence as shown in SEQ ID NO:
• 3 comprising a S to V substitution in CDR3 at position 106 of the sequence as shown in SEQ ID NO:
• 4 and a S to A substitution in CDR3 at position 108 of the sequence as shown in SEQ ID NO:
• 4, or a CDR1 sequence as shown in SEQ ID NO:
• 1, a CDR2 sequence as shown in SEQ ID NO:
• 2, and a CDR3 sequence as shown in SEQ ID NO:
• 3 comprising a A to T substitution in CDR3 at position 107 of the sequence as shown in SEQ ID NO:
• 4, or a CDR1 sequence as shown in SEQ ID NO:
• 1, a CDR2 sequence as shown in SEQ ID NO:
• 2 comprising a G to D substitution in CDR2 at position 56 of the sequence as shown in SEQ ID NO:
• 4, a N to S substitution in CDR2 at position 57 of the sequence as shown in SEQ ID NO:
• 4, and S to T substitution in CDR2 at position 58 of the sequence as shown in SEQ ID NO:
• 4, and a CDR3 sequence as shown in SEQ ID NO:
• 3.

An isolated binding agent comprising a first (VH) single domain antibody that binds to human LAG-3 and a second (VH) single domain antibody that binds to human LAG-3, wherein the first and/or second (VH) single domain antibody that binds to human LAG-3 comprises a sequence a shown in SEQ ID NO:

• 4 comprising a S23A substitution or a sequence a shown in SEQ ID NO:
• 4 comprising S23A, N57S, and S58T substitutions or a sequence a shown in SEQ ID NO:
• 4 comprising S23A and N54I substitutions or a sequence a shown in SEQ ID NO:
• 4 comprising S23A, D30N, Y32F, and S58T substitutions or a sequence a shown in SEQ ID NO:
• 4 comprising S23A, Y32F, G55S, G56D, N57I, S58T, and G59A substitutions or a sequence a shown in SEQ ID NO:
• 4 comprising S23A, Y32F, S58T, S106V, and S108A substitutions or a sequence a shown in SEQ ID NO:
• 4 comprising S23A, D30N, and A107T substitutions or a sequence a shown in SEQ ID NO:
• 4 comprising S23A, Y95H, G56D, N57S, and S58T substitutions or a sequence a shown in SEQ ID NO:
• 8.