Interleukin-12 targeted to oncofoetal fibronectin
The invention provides a compound comprising a target specific portion and an effector portion wherein the target specific portion comprises or consists of a monoclonal antibody having specificity for oncofoetal fibronectin, or a fragment or variant thereof which retains the antigen binding specificity of the parent monoclonal antibody and the effector portion comprises or consists of interleukin-12, or a functional fragment or variant thereof, characterized in the monoclonal antibody having specificity for oncofoetal fibronectin binds to a region of oncofoetal fibronectin other than the ED-B region. The invention further provides nucleic acids encoding the compounds of the invention, and the use of such compounds in medicine, e.g. in the treatment of cancer.
1. A compound comprising a target specific portion and an effector portion wherein:
(i) the target specific portion comprises a monoclonal antibody having specificity for oncofoetal fibronectin, or a fragment or variant thereof which retains the binding specificity for oncofoetal fibronectin of the parent monoclonal antibody; and
(ii) the effector portion comprises interleukin-12, or a functional fragment or variant thereof;
wherein the target specific portion is capable of binding an amino acid sequence within the repeat 7 domain of fibronectin,
wherein the compound comprises one or more polypeptides selected from the group consisting of the polypeptide of SEQ ID NO: 6 and the polypeptide of SEQ ID NO: 7, and wherein
SEQ ID NO: 6 includes SEQ ID NO: 1 and SEQ ID NO: 3; and
SEQ ID NO: 7 includes SEQ ID NO: 2.
2. A compound according to claim 1 wherein the compound comprises the polypeptide of SEQ ID NO:6 and the polypeptide of SEQ ID NO:7.
3. A compound according to claim 1 further comprising the polypeptide of SEQ ID NO:4 linked by at least one disulphide bond to the polypeptide of SEQ ID NO:6.
4. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
5. A pharmaceutical composition according to claim 4 wherein the composition is suitable for parenteral administration.
6. A compound according to claim 1 ,
wherein the compound comprises the polypeptide of SEQ ID NO: 6, and further wherein:
the target specific portion further includes the polypeptide of SEQ ID NO: 2; and
the effector portion further includes the polypeptide of SEQ ID NO: 4 conjugated to SEQ ID NO: 3 by at least one disulphide bond;
and wherein the target specific portion is fused to the effector portion via the linker sequence that comprises the amino acid sequence ATATPGAA (SEQ ID NO: 5).
7. A compound according to claim 1 , comprising:
the polypeptide of SEQ ID NO: 6;
the polypeptide of SEQ ID NO: 7 conjugated to the polypeptide SEQ ID NO: 6 by at least one disulphide bond; and
the polypeptide of SEQ ID NO: 4 conjugated to the polypeptide SEQ ID NO: 6 by a disulphide bond.
8. A compound comprising a target specific portion and an effector portion wherein:
(i) the target specific portion comprises a monoclonal antibody having specificity for oncofoetal fibronectin, or a fragment or variant thereof which retains the binding specificity for oncofoetal fibronectin of the parent monoclonal antibody; and
(ii) the effector portion comprises interleukin-12, or a functional fragment or variant thereof;
wherein the target specific portion is capable of binding an amino acid sequence within the repeat 7 domain of fibronectin, wherein:
the target specific portion comprises:
the polypeptide of SEQ ID NO: 1; and;
the polypeptide of SEQ ID NO: 2; and
the effector portion comprises:
an IL12p35 domain; and
an IL12p40 domain conjugated to the IL12p35 domain by at least one disulphide bond;
and wherein the target specific portion is fused to the effector portion via the linker sequence that comprises the amino acid sequence ATATPGAA (SEQ ID NO: 5).
9. The compound of claim 8 , wherein the compound comprises a polypeptide selected from the group consisting of the polypeptide of SEQ ID NO: 6 and the polypeptide of SEQ ID NO: 7.
10. The compound of claim 1 , wherein the compound comprises the polypeptide of SEQ ID NO: 7, and further wherein:
the target specific portion further includes includes:
the polypeptide of SEQ ID NO: 1; and
the effector portion comprises:
the polypeptide of SEQ ID NO: 3; and
the polypeptide of SEQ ID NO: 4 conjugated to SEQ ID NO: 3 by at least one disulphide bond;
and wherein the target specific portion is fused to the effector portion via the linker sequence that comprises the amino acid sequence ATATPGAA (SEQ ID NO: 5).