Office Action 1: Non-Final Rejection (2024-10-01)
Rejection types: Double Patenting

CLAIMS:
Amendments to the Claims

Please replace the claims as filed with the claims set forth below. This listing of claims will replace all prior versions, and listings, of claims in the application:

1\. - 59. (Cancelled) 258

60\. (New) A method of forcing programmed cell death protein ligand-1 (PD-L1), expressed on the surface of a breast cancer cell, to degrade in a lysosome comprising the step of physically linking PD-L1 to prolactin receptor (PRLR) by contacting the breast cancer cell with an antibody that comprises (a) an antigen-binding fragment of an anti-PD-L1 antibody and (b) an antigen-binding fragment of an anti-PRLR antibody, wherein the antibody binds to PD-L1 and PRLR on the same breast cancer cell;
wherein PD-L1 is transported to a lysosome through its physical linkage to PRLR and degraded; and
wherein the lysosomal degradation of PD-L1 through its physical linkage to PRLR is greater than the lysosomal degradation of PD-L1 not physically linked to PRLR.

61\. (New) The method of claim 60, wherein the antibody is a bispecific antibody.

62\. (New) The method of claim 60, wherein the breast cancer cell is in vivo.

63\. (New) The method of claim 61, wherein the bispecific antibody is an anti-PD-L1 x anti- PRLR bispecific antibody.

64\. (New) A method of killing a breast cancer cell that expresses on its surface a PD-L1 molecule and a PRLR destroyer molecule, the method comprising the steps of:
(i) contacting the breast cancer cell with an anti-PD-L1 bivalent monospecific antibody conjugated to a cytotoxic agent, and
(ii) physically linking PD-L1 to PRLR on the breast cancer cell of part (i) by contacting the cell with an antibody that comprises (a) an antigen-binding fragment of an anti-PD-L1 antibody and (b) an antigen-binding fragment of an anti-PRLR antibody for simultaneous binding to PD-L1 and PRLR on the same cell, wherein the PD-L1 molecule and the cytotoxic agent are subsequently transported to a lysosome within the breast cancer cell through the physical linkage between the PD-L1 molecule and the PRLR destroyer molecule.

65\. (New) The method of claim 64, wherein the cytotoxic agent is a radioisotope, a toxin, or
a drug.

66\. (New) The method of claim 65, wherein the toxin is a calicheamicin, an auristatin or a maytansine-based cytotoxin.

67\. (New) The method of claim 64, wherein the breast cancer cell is a T47D cell.

68\. (New) The method of claim 64, wherein the breast cancer cell is in vivo.

69\. (New) The method of claim 64, wherein cell-killing potency of the cytotoxic agent is enhanced by the presence of the antibody.

70\. (New) The method of claim 64, wherein the antibody that physically links PD-L1 with PRLR is a bispecific antibody.

71\. (New) A method of inhibiting the growth or promoting the regression of a tumor that comprises a breast cancer cell that expresses on its surface both a PD-L1 molecule and a PRLR destroyer molecule, the method comprising killing the breast cancer cell according to the method of claim 64.

72\. (New) The method of claim 71, wherein the antibody that physically links PD-L1 with PRLR is an anti-PD-L1 x anti-PRLR bispecific antibody.

73\. (New) The method of claim 71, wherein the cytotoxic agent is a maytansinoid-based cytotoxin.
74\. (New) A method of killing a breast cancer cell that expresses on its surface a PD-L1 molecule and a PRLR destroyer molecule, the method comprising the step of physically linking PD-L1 to PRLR by contacting the cell with an antibody cytotoxic agent conjugate that comprises (a) an antigen-binding fragment of an anti-PD-L1 antibody, (b) an antigen-binding fragment of an anti-PRLR antibody, and (c) a cytotoxic agent, wherein the PD-L1 molecule and the cytotoxic agent, through the physical linkage between the PD-L1 molecule and the PRLR destroyer molecule, are subsequently transported to a lysosome within the breast cancer cell.

75\. (New) The method of claim 74, wherein the cytotoxic agent is a radioisotope, a toxin, or
a drug.

76\. (New) The method of claim 75, wherein the toxin is a calicheamicin, an auristatin, or a maytansine-based cytotoxin.

77\. (New) The method of claim 74, wherein the breast cancer cell is a T47D cell.

78\. (New) The method of claim 74, wherein the breast cancer cell is in vivo.

79\. (New) The method of claim 74, wherein cell-killing potency of the cytotoxic agent is enhanced by the presence of the antibody.

80\. (New) The method of claim 74, wherein the antibody cytotoxic agent conjugate comprises an anti-PD-L1 x anti-PRLR bispecific antibody.

81\. (New) A method of inhibiting the growth or promoting the regression of a tumor that comprises a breast cancer cell that expresses on its surface both a PD-L1 molecule and a PRLR destroyer molecule, the method comprising killing the breast cancer cell according to the method of claim 74.

82\. (New) The method of claim 81, wherein the cytotoxic agent is a maytansinoid-based cytotoxin.

83\. (New) The method of claim 81, wherein the antibody cytotoxic agent conjugate comprises an anti-PD-L1 x anti-PRLR bispecific antibody.

84\. (New) A method of forcing PD-L1, expressed on the surface of a breast cancer cell, to degrade in a lysosome comprising the step of physically linking PD-L1 to PRLR by contacting the breast cancer cell with an antibody that comprises (a) an antigen-binding fragment of an anti- PD-L1 antibody and (b) an antigen-binding fragment of an anti-PRLR antibody, wherein the antibody binds to PD-L1 and PRLR on the same breast cancer cell;
wherein PD-L1 is transported to a lysosome through its physical linkage to PRLR and degraded; and
wherein, in the presence of an inhibitor of protein synthesis, at least about 40% of PD-L1 in the breast cancer cell is degraded after about 2 hours of contacting the breast cancer cell with the antibody; and/or
in the presence of an inhibitor of protein synthesis, at least about 80% of PD-L1 in the breast cancer cell is degraded after about 4 hours of contacting the breast cancer cell with the antibody.

85\. (New) The method of claim 84, wherein the antibody is a bispecific antibody.

86\. (New) The method of claim 85, wherein the bispecific antibody is an anti-PD-L1 x anti- PRLR bispecific antibody.

87\. (New) A method of forcing PD-L1, expressed on the surface of a breast cancer cell, to degrade in a lysosome comprising the step of physically linking PD-L1 to PRLR by contacting the breast cancer cell with an antibody that comprises (a) an antigen-binding fragment of an anti- PD-L1 antibody and (b) an antigen-binding fragment of an anti-PRLR antibody, wherein the antibody binds to PD-L1 and PRLR on the same breast cancer cell;
wherein PD-L1 is transported to a lysosome through its physical linkage to PRLR and degraded; and wherein degradation of PD-L1 is dependent on the dose of the antibody.

88\. (New) The method of claim 87, wherein the antibody is a bispecific antibody.

89\. (New) The method of claim 88, wherein the bispecific antibody is an anti-PD-L1 x anti- PRLR bispecific antibody.
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OFFICE ACTION:
DETAILED ACTION
Notice of Pre-AIA  or AIA  Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-59 are canceled.  Claims 60-89 have been added and are examined on the merits.
Specification
The specification was amended  on 11/22/2021 to state that this application is a Divisional of 15/202,822.  However, the requirement for Election of Species in ‘822 was withdrawn in the Office action of 10/19/2018.  Thus, the instant application is not a Division of 15/202,822, but rather a Continuation.
Appropriate correction is required.
It is noted that Section 804.01 of the M.P.E.P. enumerates situations wherein  the prohibition against nonstatutory double patenting rejections under 35 U.S.C. 121  does not apply:
(E) The requirement for restriction was withdrawn, in its entirety or in pertinent part, by the examiner before the patent issues.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA  as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 60-89 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11,129,903 in view of Hassan et al (Expert Opinion on therapeutic Targets, 2011, vol. 15, pp. 1211-1225).
Claims 1-30 of the ‘903 patent teach the limitations of the instant claims with the exception that Her2 is physically linked to PRLR, rather than PD-L1 as required in the instant claims.  The claims of the patent  teach that the method forces the degradation of Her2 (claim 1), kills a breast cancer cell that expresses Her2 on the surface (claim 5), inhibits the growth  or promotes the regression of a tumor comprising breast cancer cells that express both of Her2 and PRLR (claim 12).  The claims of the patent do not teach a method for forcing the degradation of PD-L1, a method for killing a breast cancer cell that expresses PD-L1 on the surface, a method for inhibiting the growth  or promoting the regression of a tumor comprising breast cancer cells that express both of PD-L1 and PRLR.
Hasan et al teach that cell surface B7-H1/PD-L1 expressed on breast cancer cells is associated with high-risk prognostic factors (page 1212, “box”).  Hasan et al teach that B7-H1 recruits regulatory T cells into the tumor microenvironment, and that B7-H1 is a promising therapeutic target for the treatment of breast cancer patients (page 1212, “box”).  Hasan et al teach that one approach is to selectively disrupt B7-H1 signaling on tumor cells (page 1219, lines 5-8 under the heading “5.3 Genetic Manipulation of B7-H1 expression by silencing RNA and gene transfection”).
It would have been prima facie obvious prior to the effective filing date to substitute B7-H1 /PD-L1 for Her2 in the ‘903 claims.  One of skill in the art would have been motivated to do so by the teachings of Hassan et al on  the need for disrupting B7-H1 on breast tumor cells.
Claims 60-83 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of U.S. Patent No. 11,191,844 in view of Hassan et al (Expert Opinion on therapeutic Targets, 2011, vol. 15, pp. 1211-1225).
Claims 1-29 of the ‘844 patent teach the limitations of the instant claims with the exception that tumor antigen is physically linked to PRLR, rather than PD-L1 as required in the instant claims.  The claims of the patent  teach that the method forces the degradation of Her2 (claim 1), kills a breast cancer cell that expresses Her on the surface (claim 6), inhibits the growth  or promotes the regression of a tumor comprising breast cancer cells that express both of Her2 and PRLR (claim 18).  The claims of the patent do not teach a method for forcing the degradation of PD-L1, a method for killing a breast cancer cell that expresses PD-L1 on the surface, a method for inhibiting the growth  or promoting the regression of a tumor comprising breast cancer cells that express both of PD-L1 and PRLR.
Hasan et al teach that cell surface B7-H1/PD-L1 expressed on breast cancer cells is associated with high-risk prognostic factors (page 1212, “box”).  Hasan et al teach that B7-H1 recruits regulatory T cells into the tumor microenvironment, and that B7-H1 is a promising therapeutic target for the treatment of breast cancer patients (page 1212, “box”).  Hasan et al teach that one approach is to selectively disrupt B7-H1 signaling on tumor cells (page 1219, lines 5-8 under the heading “5.3 Genetic Manipulation of B7-H1 expression by silencing RNA and gene transfection”).
It would have been prima facie obvious prior to the effective filing date to substitute B7-H1 /PD-L1 for the tumor antigen in the ‘844 claims.  One of skill in the art would have been motivated to do so by the teachings of Hassan et al on  the need for disrupting B7-H1 on breast tumor cells.
All claims are rejected.


NEXT OFFICE ACTION: Reasons for Allowance
The following is an examiner’s statement of reasons for allowance: Cygnar et al (WO2013/138400, reference of the IDS filed 9/23/2021) teach therapeutic methods comprising (a) a toxin- or drug-conjugated antigen-binding molecule that specifically binds a tumor-associated antigen; and (b) a multi-specific antigen-binding molecule comprising (i) a first binding domain that specifically binds an internalizing effector protein  and (ii) a second binding domain that specifically binds the toxin- or drug-conjugated antigen-binding molecule. In this embodiment, the multi-specific antigen-binding molecule functions to link the toxin- or drug-conjugated antigen-binding molecule to the internalizing effector protein, which thereby functions to physically link the tumor associated antigen to the internalizing effector protein.  Cygnar et al teach that internalization of the toxin-labeled anti-tumor-associated antigen antibody via its connection to the internalizing effector protein would consequently result in targeted tumor cell killing (paragraph [0061]).
Cygnar et al teach that the simultaneous binding of a multi-specific antigen-binding molecule to an internalizing effector protein and a tumor-associated antigen will result in preferential internalization of the multi-specific antigen-binding molecule into tumor cells. Cygnar et al teach that if the multi-specific antigen-binding molecule is conjugated to a drug, toxin or radioisotope or if the multi-specific antigen-binding molecule is administered in combination with an accomplice antibody that is conjugated to a drug, toxin or radioisotope, the targeted internalization of the tumor-associated antigen into the tumor cell via its linkage to the multi-specific antigen-binding molecule, will result in extremely specific tumor cell killing (paragraph [0064]).
Cygnar et al teach that cell surface expressed target proteins include tumor associated antigens such as AFP, ALK, BAGE proteins, β-catenin, brc-abl, BRCA1 , BORIS, CA9, carbonic anhydrase IX, caspase-8, CD40, CDK4, CEA, CTLA4, cyclin-B1 , CYP1 B1 , EGFR, EGFRvll l, ErbB2/Her2, ErbB3, ErbB4, ETV6-AML, EphA2, Fra-1 , FOLR1 , GAGE proteins, GD2, GD3, GloboH, glypican-3, GM3, gp100, Her2, HLA/B-raf, HLA/k-ras, HLA MAGE-A3, hTERT, LMP2, MAGE, MART-1 , mesothelin, ML-IAP, Mud , Mud 6 (), MU M1 , NA17, NY-BR1 , NY-BR62, NY-BR85, NY-ES01, OX40, p15, p53, PAP, PAX3, PAX5, PCTA-1, PLAC1 , PRLR, PRAME, PSMA, RAGE proteins, Ras, RGS5, Rho, SART-1, SART-3, Steap-1 , Steap-2, survivin, TAG-72, TGF-β, TMPRSS2, Tn, TRP-1 , TRP-2, tyrosinase, and uroplakin-3. (paragraph [0059]).  Although Cygnar et al teach PRLR as a cell surface expressed tumor associated antigen, Cygnar et al do not teach PRLR as an internalizing effector protein.
Piccirilli et al (WO2008/014404, reference of the IDS filed 9/23/2021) teach a method of delivering an agent to a cell comprising a prolactin receptor, the method comprising contacting the cell with a complex comprising the agent coupled to a prolactin receptor ligand wherein the agent is, in part, a cytotoxic moiety (claims 1 and 2 of ‘404).  Piccirilli et al do not teach that part of the external domain of a non-prolactin receptor such as PD-L1 on the same cell as the PRLR can be delivered to the cell via the prolactin receptor endocytic pathway.  Piccirilli et al do not teach that the cargo internalized by the prolactin receptor is directed toward the lysosomal pathway in the cell.
Varghese et al (Molecular and Cellular Biology, 2008, Vol. 28, pp. 5275-5287, reference of the IDS filed 9/23/2021) teach that the data regarding lysosomal versus proteasomal pathways for the degradation of PRLR is controversial (page 5278, first column, lines 1-4 under “Results”).  Varghese et al that prolactin binding to PRLR stimulates PRLR ubiquitination and leads to PRLR internalization, sorting to the lysosomes and lysosomal degradation (page 5276, first column, lines 1-3 of the second full paragraph).  Varghese et al are silent regarding cargo bound to the internalized PRLR with respect to sorting the cargo-bound PRLR into the lysosomes for lysosomal degradation versus proteasomal degradation.
Thus, the prior art does not teach or suggest that PD-L1, or PD-L1 bound to a cytotoxic cargo can be transported and degraded in a lysosome through physical linkage of  the PD-L1 receptor to PRLR.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee.  Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”

CITED REFERENCE SUMMARIES: Ref US11129903: Claims:
1. A method of forcing HER2, expressed on the surface of a breast cancer cell, to degrade in a lysosome comprising the step of physically linking HER2 to PRLR by contacting the breast cancer cell with an antibody that comprises (a) an antigen-binding fragment of an anti-HER2 antibody and (b) an antigen-binding fragment of an anti-PRLR antibody,
wherein the antibody binds to HER2 and PRLR on the same breast cancer cell;
wherein HER2 is transported to a lysosome through its physical linkage to PRLR and degraded; and
wherein the lysosomal degradation of HER2 through its physical linkage to PRLR is greater than the lysosomal degradation of HER2 not physically linked to PRLR.
2. The method of claim 1, wherein the antibody is a bispecific antibody.
3. The method of claim 1, wherein the breast cancer cell is in vivo.
4. The method of claim 2, wherein the bispecific antibody is an anti-HER2 x anti-PRLR bispecific antibody.
5. A method of killing a breast cancer cell that expresses on its surface a Her2 molecule and a PRLR destroyer molecule, the method comprising the steps of:
(i) contacting the breast cancer cell with an anti-Her2 bivalent monospecific antibody conjugated to a cytotoxic agent, and
(ii) physically linking Her2 to PRLR on the breast cancer cell of part (i) by contacting the cell with an antibody that comprises (a) an antigen-binding fragment of an anti-Her2 antibody and (b) an antigen-binding fragment of an anti-PRLR antibody for simultaneous binding to Her2 and PRLR on the same cell, wherein the wherein the Her2 molecule and the cytotoxic agent are subsequently transported to a lysosome within the breast cancer cell through the physical linkage between the Her2 molecule and the PRLR destroyer molecule; and wherein the breast cancer cell expresses Her2 at a level assessed by immunohistochemistry as IHC2+ or IHC3+.
6. The method of claim 5, wherein the cytotoxic agent is a radioisotope, a toxin, or a drug.
7. The method of claim 6, wherein the toxin is a calicheamicin, an auristatin or a maytansine-based cytotoxin.
8. The method of claim 5, wherein the breast cancer cell is a T47D cell.
9. The method of claim 5, wherein the breast cancer cell is in vivo.
10. The method of claim 5, wherein cell-killing potency of the cytotoxic agent is enhanced by the presence of the antibody.
11. The method of claim 5, wherein the antibody that physically links HER2 with PRLR is a bispecific antibody.
12. A method of inhibiting the growth or promoting the regression of a tumor that comprises a breast cancer cell that expresses on its surface both a HER2 molecule and a PRLR destroyer molecule, the method comprising killing the breast cancer cell according to the method of claim 5.
13. The method of claim 12, wherein the antibody that physically links HER2 with PRLR is an anti-HER2 x anti-PRLR bispecific antibody.
14. The method of claim 12, wherein the cytotoxic agent is a maytansinoid-based cytotoxin.
15. A method of killing a breast cancer cell that expresses on its surface a HER2 molecule and a PRLR destroyer molecule, the method comprising the step of physically linking HER2 to PRLR by contacting the cell with an antibody cytotoxic agent conjugate that comprises (a) an antigen-binding fragment of an anti-HER2 antibody, (b) an antigen-binding fragment of an anti-PRLR antibody, and (c) a cytotoxic agent,
wherein the HER2 molecule and the cytotoxic agent, through the physical linkage between the HER2 molecule and the PRLR destroyer molecule, are subsequently transported to a lysosome within the breast cancer cell; and
wherein the breast cancer cell expresses HER2 at a level assessed by immunohistochemistry as IHC2+ or IHC3+.
16. The method of claim 15, wherein the cytotoxic agent is a radioisotope, a toxin, or a drug.
17. The method of claim 16, wherein the toxin is a calicheamicin, an auristatin, or a maytansine-based cytotoxin.
18. The method of claim 15, wherein the breast cancer cell is a T47D cell.
19. The method of claim 15, wherein the breast cancer cell is in vivo.
20. The method of claim 15, wherein cell-killing potency of the cytotoxic agent is enhanced by the presence of the antibody.
21. The method of claim 15, wherein the antibody cytotoxic agent conjugate comprises an anti-HER2 x anti-PRLR bispecific antibody.
22. A method of inhibiting the growth or promoting the regression of a tumor that comprises a breast cancer cell that expresses on its surface both a HER2 molecule and a PRLR destroyer molecule, the method comprising killing the breast cancer cell according to the method of claim 15.
23. The method of claim 22, wherein the cytotoxic agent is a maytansinoid-based cytotoxin.
24. The method of claim 22, wherein the antibody cytotoxic agent conjugate comprises an anti-HER2 x anti-PRLR bispecific antibody.
25. A method of forcing HER2, expressed on the surface of a breast cancer cell, to degrade in a lysosome comprising the step of physically linking HER2 to PRLR by contacting the breast cancer cell with an antibody that comprises (a) an antigen-binding fragment of an anti-HER2 antibody and (b) an antigen-binding fragment of an anti-PRLR antibody,
wherein the antibody binds to HER2 and PRLR on the same breast cancer cell;
wherein HER2 is transported to a lysosome through its physical linkage to PRLR and degraded; and
wherein,
in the presence of an inhibitor of protein synthesis, at least about 40% of HER2 in the breast cancer cell is degraded after about 2 hours of contacting the breast cancer cell with the antibody; and/or
in the presence of an inhibitor of protein synthesis, at least about 80% of HER2 in the breast cancer cell is degraded after about 4 hours of contacting the breast cancer cell with the antibody.
26. The method of claim 25, wherein the antibody is a bispecific antibody.
27. The method of claim 26, wherein the bispecific antibody is an anti-HER2 x anti-PRLR bispecific antibody.
28. A method of forcing HER2, expressed on the surface of a breast cancer cell, to degrade in a lysosome comprising the step of physically linking HER2 to PRLR by contacting the breast cancer cell with an antibody that comprises (a) an antigen-binding fragment of an anti-HER2 antibody and (b) an antigen-binding fragment of an anti-PRLR antibody,
wherein the antibody binds to HER2 and PRLR on the same breast cancer cell;
wherein HER2 is transported to a lysosome through its physical linkage to PRLR and degraded; and
wherein degradation of HER2 is dependent on the dose of the antibody.
29. The method of claim 28, wherein the antibody is a bispecific antibody.
30. The method of claim 29, wherein the bispecific antibody is an anti-HER2 x anti-PRLR bispecific antibody.
Ref US11191844: Claims:
1. A method of forcing the degradation in a lysosome of a tumor-associated antigen (TAA) expressed on the surface of a breast cancer cell comprising the step of physically linking the TAA to a prolactin receptor (PRLR) by contacting the breast cancer cell with a multispecific antigen-binding protein that comprises (a) an antigen-binding fragment of an anti-TAA antibody and (b) an antigen-binding fragment of an anti-PRLR antibody,
wherein the TAA is selected from the group consisting of AFP, ALK, β-catenin, CA9, CD40, CEA, EGFR, ErbB3, ErbB4, EphA2, FOLR1, GD3, GloboH, a MAGE protein, mesothelin, Muc1, and PRAME,
wherein the multispecific antigen-binding protein binds to the TAA and PRLR on the same breast cancer cell, and
wherein the TAA is transported to a lysosome through its physical linkage to PRLR and degraded.
2. The method of claim 1, wherein the multispecific antigen-binding protein is a bispecific antibody.
3. The method of claim 1, wherein the breast cancer cell is in vivo.
4. The method of claim 1, wherein the PRLR expressed on the surface of the breast cancer cell undergoes constitutive surface turnover.
5. The method of claim 1, wherein the breast cancer cell is a T47D cell.
6. A method of killing a breast cancer cell that expresses on its surface a TAA molecule and a PRLR destroyer molecule, the method comprising the steps of:
(i) contacting the breast cancer cell with an anti-TAA bivalent monospecific antibody conjugated to a cytotoxic agent, and
(ii) physically linking the TAA to the PRLR destroyer molecule on the breast cancer cell of part (i) by contacting the cell with an antibody that comprises (a) an antigen-binding fragment of an anti-TAA antibody and (b) an antigen-binding fragment of an anti-PRLR antibody for simultaneous binding to the TAA and PRLR on the same cell,
wherein the TAA molecule and the cytotoxic agent, through the physical linkage between the TAA molecule and the PRLR destroyer molecule, are subsequently transported to a lysosome within the breast cancer cell, thus forcing the degradation of the TAA, and
wherein the TAA is selected from the group consisting of AFP, ALK, β-catenin, CA9, CD40, CEA, EGFR, ErbB3, ErbB4, EphA2, FOLR1, GD3, GloboH, a MAGE protein, mesothelin, Muc1, and PRAME.
7. The method of claim 6, wherein the PRLR destroyer molecule expressed on the surface of the breast cancer cell undergoes constitutive surface turnover.
8. The method of claim 6, wherein the breast cancer cell is a T47D cell.
9. The method of claim 6, wherein the breast cancer cell is in vivo.
10. The method of claim 6, wherein cell-killing potency of the cytotoxic agent is enhanced by the presence of the antibody.
11. The method of claim 6, wherein the antibody that physicall links the TAA and the PRLR is a bispecific antibody.
12. The method of claim 6, wherein the cytotoxic agent is a radioisotope, a toxin, or a drug.
13. The method of claim 12, wherein the toxin is a calicheamicin, an auristatin or a maytansine-based cytotoxin.
14. A method of killing a breast cancer cell that expresses on its surface a TAA molecule and a PRLR destroyer molecule, the method comprising the step of physically linking the TAA to the PRLR by contacting the cell with an antibody cytotoxic agent conjugate that comprises (a) an antigen-binding fragment of an anti-TAA antibody, (b) an antigen-binding fragment of an anti-PRLR antibody, and (c) a cytotoxic agent, for simultaneous binding to the TAA and PRLR on the same call, wherein the TAA molecule and the cytotoxic agent, through the physical linkage between the TAA molecule and the PRLR destroyer molecule, are subsequently transported to a lysosome within the breast cancer cell, thus forcing the degradation of the TAA, and
wherein the TAA is selected from the group consisting of AFP, ALK, β-catenin, CA9, CD40, CEA, EGFR, ErbB3, ErbB4, EphA2, FOLR1, GD3, GloboH, a MAGE protein, mesothelin, Muc1 and PRAME.
15. The method of claim 14, wherein the cytotoxic agent is a radioisotope, a toxin, or a drug.
16. The method of claim 15, wherein the toxin is a calicheamicin, an auristatin, or a maytansine-based cytotoxin.
17. The method of claim 14, wherein the PRLR destroyer molecule expressed on the surface of the breast cancer cell undergoes constitutive surface turnover.
18. A method of inhibiting the growth or promoting the regression of a tumor that comprises a breast cancer cell that expresses on its surface both a TAA molecule and a PRLR destroyer molecule, the method comprising killing the breast cancer cell according to the method of claim 14.
19. The method of claim 18, wherein the TAA is selected from the group consisting of ALK, EGFR, ErbB3, and ErbB4.
20. The method of claim 18, wherein the antibody cytotoxic agent conjugate comprises an anti-TAA × anti-PRLR bispecific antibody.
21. The method of claim 18, wherein the cytotoxic agent is a maytansinoid-based cytotoxin.
22. The method of claim 14, wherein the breast cancer cell is a T47D cell.
23. The method of claim 14, wherein the breast cancer cell is in vivo.
24. The method of claim 14, wherein cell-killing potency of the cytotoxic agent is enhanced by the presence of the antibody.
25. The method of claim 14, wherein the antibody cytotoxic agent conjugate comprises a bispecific antibody.
26. A method of inhibiting the growth or promoting the regression of a tumor that comprises a breast cancer cell that expresses both a TAA molecule and a PRLR destroyer molecule on its surface, the method comprising killing the breast cancer cell according to the method of claim 6.
27. The method of claim 26, wherein the TAA is selected from the group consisting of ALK, EGFR, ErbB3, and ErbB4.
28. The method of claim 26, wherein the antibody that physically links the TAA with PRLR is an anti-TAA × anti-PRLR bispecific antibody.
29. The method of claim 26, wherein the cytotoxic agent is a maytansinoid-based cytotoxin.
30. A multispecific antigen-binding protein that comprises (a) an antigen-binding fragment of an anti-TAA antibody that binds a TAA on the surface of a tumor cell and (b) an antigen-binding fragment of an anti-PRLR antibody that binds PRLR on the surface of a tumor cell,
wherein the TAA is selected from the group consisting of AFP, ALK, β-catenin, CA9, CD40, CEA, EGFR, ErbB3, ErbB4, EphA2, FOLR1, GD3, GloboH, a MAGE protein, mesothelin, Muc1, and PRAME.
31. A pharmaceutical composition comprising the multispecific antigen-binding protein of claim 30.