Radiolabeled met binding proteins for immuno-pet imaging

A method for monitoring the efficacy of an anti-cancer therapy in a subject, the method comprising:

• (a) administering a radiolabeled antibody conjugate to the subject wherein the subject has received the anti-cancer therapy;
• and
• (b) imaging localization of the radiolabeled antibody conjugate in the cancer by positron emission tomography (PET) imaging,
• wherein a decrease in the baseline in the area of localization of the radiolabeled antibody conjugate indicates cancer regression and efficacy of the anti-cancer therapy;
• and
• wherein the radiolabeled antibody conjugate comprises an antibody or antigen-binding fragment thereof that binds MET, a chelating moiety, and a positron emitter, and wherein the antibody or antigen-binding fragment thereof has one or more properties selected from the group consisting of:
• (i) comprises a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs:
• 2, 10, 18, 26, 34, 42, 50, 58, 66, 74, 82, 90, 98, 106, 114, 122, and 130, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity;
• (ii) comprises a light chain variable region (LCVR) having an amino acid sequence of SEQ ID NO:
• 138, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity;
• (iii) comprises a heavy chain complementarity determining region (HCDR)-3 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs:
• 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, 104, 112, 120, 128 and 136, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity;
• and a light chain complementarity determining region (LCDR)-3 domain having an amino acid sequence of SEQ ID NO:
• 144, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity;
• (iv) comprises an HCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs:
• 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 108, 116, 124, and 132, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity;
• an HCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs:
• 6, 14, 22, 30, 38, 46, 54, 62, 70, 78, 86, 94, 102, 110, 118, 126, and 134, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity;
• an LCDR1 domain having an amino acid sequence of SEQ ID NO:
• 140, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity;
• and an LCDR2 domain having an amino acid sequence of SEQ ID NO:
• 142, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity;
• (v) is a multi-specific antigen-binding molecule comprising a first binding specificity to MET and a second binding specificity to a tumor specific antigen;
• (vi) is a multi-specific antigen-binding molecule comprising a first binding specificity to one epitope of MET and a second binding specificity to a second epitope of MET;
• (vii) binds to monomeric human MET (e.g., hMET.mmh) with a binding dissociation equilibrium constant (KD) of less than about 230 nM as measured by surface plasmon resonance at 25° C. or 37° C.;
• (viii) binds to dimeric human MET with a KD of less than about 3 nM as measured by surface plasmon resonance at 25° C. or 37° C.;
• (ix) blocks the binding of HGF to MET;
• and
• (x) suppresses cancer growth and increases survival in subjects with cancer.

A method for predicting a positive response to an anti-cancer therapy in a subject, the method comprising:

• (a) administering a radiolabeled antibody conjugate to the subject wherein the subject has received the anti-cancer therapy;
• and
• (b) imaging localization of the radiolabeled antibody conjugate in the cancer by positron emission tomography (PET) imaging,
• wherein the presence of the radiolabeled antibody conjugate in the cancer indicates that the cancer is MET positive,
• wherein a MET positive cancer predicts a positive response to the anti-cancer therapy.

A method for predicting efficacy of an anti-cancer therapy in a subject, the method comprising:

• (a) determining the level of MET expression in the cancer comprising administering a radiolabeled conjugate to the cancer, and visualizing MET expression by PET imaging, wherein the presence of the radiolabeled antibody conjugate in the cancer indicates that the cancer is MET positive;
• and
• (b) correlating the level of MET expression with successful anti-cancer therapy,
• wherein a decrease in MET expression, relative to MET expression prior to anti-cancer therapy, is predictive of successful anti-cancer therapy.