Methods and compositions for treating cancer with von Willebrand factor peptide linked to immunotherapeutic antibodies
The methods and compositions described herein address the need in the art by providing compositions and methods for a therapy with an antibody that is specifically targeted to and/or retained intra- or peri-tumorally, limiting systemic exposure and reducing side-effects. Accordingly, aspects of the disclosure relate to a composition comprising an immunotherapeutic antibody operatively linked to an extracellular matrix (ECM)-affinity peptide. An ECM-affinity peptide is one that has affinity for an extracellular matrix protein.
1 . A composition comprising an immunotherapeutic antibody operatively linked to an extracellular matrix (ECM)-affinity peptide, wherein the ECM-affinity peptide comprises a von Willebrand factor (VWF) peptide.
2 . The composition of claim 1 , wherein the VWF peptide comprises a peptide that is at least 85% identical to SEQ ID NO:3, SEQ ID NO:11, SEQ ID NO: 14, or fragments thereof.
3 . The composition of claim 1 , wherein the immunotherapeutic antibody comprises a CTLA4, PD-L1, or PD-1 antibody.
4 . The composition of claim 1 , wherein the immunotherapeutic antibody comprises a CD40 agonistic antibody.
5 . The composition of claim 1 , wherein the composition further comprises a second immunotherapeutic antibody operatively linked to an extracellular matrix (ECM)-affinity peptide.
6 . The composition of claim 5 , wherein the composition comprises:
a CTLA4 antibody operatively linked to an ECM-affinity peptide; and
(a) a PD-L1 antibody operatively linked to an ECM-affinity peptide or (b) a PD-1 antibody operatively linked to an ECM-affinity peptide.
7 . A method for treating cancer in a subject comprising administering the composition of claim 1 to a subject.
8 . The composition of claim 1 , wherein the immunotherapeutic antibody comprises an αGITR, αCD134, or αCD137 antibody.
9 . The composition of claim 2 , wherein the VWF peptide comprises a peptide that that has the amino acid sequence of SEQ ID NO:3, SEQ ID NO:11, or SEQ ID NO: 14.
10 . The composition of claim 1 , wherein the peptide is covalently linked to the antibody.
11 . The composition of claim 1 , wherein the peptide is crosslinked to the antibody through a bifunctional linker.
12 . The composition of claim 3 , wherein the immune checkpoint inhibitory antibody comprises pembrolizumab, nivolumab, atezolizumab, ipilimumab, tremelimumab, avelumab, or durvalumab.
13 . The composition of claim 1 , wherein the antibody is a humanized antibody.
14 . The composition of claim 1 , wherein the ratio of peptide to antibody is about 1:1 to 10:1.
15 . The composition of claim 1 , wherein the VWF peptide comprises a peptide that is at least 95% identical to SEQ ID NO:14.
16 . The composition of claim 1 , wherein the VWF peptide comprises a peptide that is at least 98% identical to SEQ ID NO:14.
17 . The composition of claim 1 , wherein the VWF peptide comprises a peptide that is at least 95% identical to SEQ ID NO:14, and the immunotherapeutic antibody comprises a CTLA4 antibody.
18 . The composition of claim 1 , wherein the VWF peptide comprises a peptide that is at least 95% identical to SEQ ID NO:14, and the immunotherapeutic antibody comprises a PD-L1 antibody.
19 . The composition of claim 1 , wherein the VWF peptide comprises a peptide that is at least 95% identical to SEQ ID NO:14, and the immunotherapeutic antibody comprises a PD-1 antibody.
20 . A composition comprising an immunotherapeutic antibody operatively linked to an extracellular matrix (ECM)-affinity peptide, wherein the ECM-affinity peptide comprises a von Willebrand factor (VWF) peptide, and wherein the VWF peptide comprises a peptide that is at least 85% identical to SEQ ID NO:3, SEQ ID NO:11, SEQ ID NO: 14, or fragments thereof.