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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after allowance or after an Office action under Ex Parte Quayle, 25 USPQ 74, 453 O.G. 213 (Comm'r Pat. 1935). Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant's submission filed on 6/18/2024 has been entered.
Status of Claims
Claims 2-5, 7, 9, 11, 17, 20, 23, 24, 26 and 50-55 are pending and are examined herein on the merits for patentability.
The examiner for your application in the USPTO has changed. Examiner Leah Schlientz can be reached at 571-272-9928.
The indicated allowability of claims 2-5, 7, 9, 11, 17, 20, 23, 24, 26 and 50-55 is withdrawn in view of newly discovered reference(s) as set forth below. Rejections based on the newly cited reference(s) follow.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 2-5, 7, 9, 11, 17, 20, 23, 24, 26 and 50-55 are rejected under 35 U.S.C. 103 as being unpatentable over Giurleo et al. (US 2019/0023790) in view of Bryans et al. (US 2008/0188478).
Giurleo teaches methods for monitoring the efficacy of an anti-tumor therapy in a subject, wherein the methods comprise selecting a subject with a solid tumor wherein the subject is being treated with an anti-tumor therapy; administering a radiolabeled anti-CD8 conjugate described herein to the subject; imaging the localization of the administered radiolabeled conjugate in the tumor by PET imaging; and determining tumor growth, wherein a decrease from the baseline in uptake of the conjugate or radiolabeled signal indicates efficacy of the anti-tumor therapy. In certain embodiments, the anti-tumor therapy comprises a PD-1 inhibitor (e.g., REGN2810, BGB-A317, nivolumab, pidilizumab, and pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, MDX-1105, and REGN3504, as well as those disclosed in Patent Publication No. US 2015-0203580), CTLA-4 inhibitor (e.g., ipilimumab), a TIM3 inhibitor, a BTLA inhibitor, a TIGIT inhibitor, a CD47 inhibitor, a GITR inhibitor, an antagonist of another T cell co-inhibitor or ligand (e.g., an antibody to LAG3, CD-28, 2B4, LY108, LAIR1, ICOS, CD160 or VISTA), an indoleamine-2,3-dioxygenase (IDO) inhibitor, a vascular endothelial growth factor (VEGF) antagonist [e.g., a “VEGF-Trap” such as aflibercept or other VEGF-inhibiting fusion protein as set forth in U.S. Pat. No. 7,087,411, or an anti-VEGF antibody or antigen-binding fragment thereof (e.g., bevacizumab, or ranibizumab) or a small molecule kinase inhibitor of VEGF receptor (e.g., sunitinib, sorafenib, or pazopanib)], an Ang2 inhibitor (e.g., nesvacumab), a transforming growth factor beta (TGFβ) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor (e.g., erlotinib, cetuximab), a CD20 inhibitor (e.g., an anti-CD20 antibody such as rituximab), an antibody to a tumor-specific antigen [e.g., CA9, CA125, melanoma-associated antigen 3 (MAGE3), carcinoembryonic antigen (CEA), vimentin, tumor-M2-PK, prostate-specific antigen (PSA), mucin-1, MART-1, and CA19-9], a vaccine (e.g., Bacillus Calmette-Guerin, a cancer vaccine), an adjuvant to increase antigen presentation (e.g., granulocyte-macrophage colony-stimulating factor), a bispecific antibody (e.g., CD3×CD20 bispecific antibody, or PSMA×CD3 bispecific antibody), a cytotoxin, a chemotherapeutic agent (e.g., dacarbazine, temozolomide, cyclophosphamide, docetaxel, doxorubicin, daunorubicin, cisplatin, carboplatin, gemcitabine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, and vincristine), cyclophosphamide, radiotherapy, an IL-6R inhibitor (e.g., sarilumab), an IL-4R inhibitor (e.g., dupilumab), an IL-10 inhibitor, a cytokine such as IL-2, IL-7, IL-21, and IL-15, and an antibody-drug conjugate (ADC) (e.g., anti-CD19-DM4 ADC, and anti-DS6-DM4 ADC) (paragraph 0039).
Exemplary anti-CD8 antibodies are listed in Table 1, which provides the amino acid sequence identifiers and nucleic acid sequence identifiers of the heavy and light chain complementarity determining region sequences and heavy and light chain variable region sequences (paragraph 0011).
Provided are methods for predicting response of a subject to an anti-tumor therapy, the methods comprising selecting a subject with a solid tumor; and determining if the tumor is CD8 positive, wherein if the tumor is CD8 positive it predicts a positive response of the subject to an anti-tumor therapy. In certain embodiments, the tumor is determined positive by administering a radiolabeled anti-CD8 antibody conjugate of the present disclosure and localizing the radiolabeled antibody conjugate in the tumor by PET imaging wherein presence of the radiolabeled antibody conjugate in the tumor indicates that the tumor is CD8 positive. In some embodiments, the anti-tumor therapy is selected from a PD-1 inhibitor (e.g., REGN2810, BGB-A317, nivolumab, pidilizumab, and pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, MDX-1105, and REGN3504), CTLA-4 inhibitor (e.g., ipilimumab), … etc (paragraph 0040).
Provided are methods of imaging a tissue comprising CD8-expressing cells, for example, CD8-expressing intratumoral lymphocytes, or CD8 positive T cells, the methods comprising administering a radiolabeled anti-CD8 antibody conjugate described herein to the tissue, and visualizing the CD8 expression by PET imaging (paragraph 0034).
Provided are methods for predicting a positive response to an anti-tumor therapy in a subject with a solid tumor. The methods comprise administering a radiolabeled anti-CD8 antibody conjugate to the subject to determine the presence of CD8 positive cells in the solid tumor; wherein the presence of CD8 positive cells predicts a positive response to an anti-tumor therapy (paragraph 0041).
Provided are methods for monitoring a positive response to an anti-tumor therapy in a subject with a solid tumor. The methods comprise (a) administering one or more doses of an anti-tumor therapy to the subject; and (b) administering a radiolabeled anti-CD8 antibody conjugate to the subject 1 to 20 weeks after administration of the anti-tumor therapy to determine the presence of CD8 positive cells in the solid tumor. The presence of CD8 positive cells indicates a positive response to the anti-tumor therapy (paragraph 0042).
Provided are methods for predicting or monitoring success or efficacy of anti-tumor therapy in a subject with a solid tumor, the method comprising: (a) determining the level of CD8 positive cells in the tumor; and (b) correlating the level of CD8 positive cells with successful anti-tumor therapy. An elevated level of CD8 above a certain threshold is predictive or indicative of successful anti-tumor therapy (paragraph 0043).
Provided are methods for monitoring T-cell presence or T-cell infiltration in a tumor over time, the method comprising: (a) administering a radiolabeled anti-CD8 antibody conjugate at a first timepoint to a subject having the tumor and determining the presence of CD8 positive T-cells in the tumor; (b) administering one or more doses of an anti-tumor therapy to the subject; and (c) administering a radiolabeled anti-CD8 antibody conjugate at a second timepoint to the subject 1 to 20 weeks after administration of the anti-tumor therapy and determining the presence of CD8 positive T-cells in the tumor. The presence of T-cells in the tumor is indicative of a positive response to the anti-tumor therapy (paragraph 0044).
Suitable positron emitters include, but are not limited to, those that form stable complexes with the chelating moiety and have physical half-lives suitable for immuno-PET imaging purposes. Illustrative positron emitters include, but are not limited to 89Zr, 68Ga, 64Cu, 44Sc, and 86Y. Suitable positron emitters also include those that directly bond with the CD8 binding protein, including, but not limited to 76Br and 124I (paragraph 0161).
According to one aspect, the present disclosure provides methods of imaging a tissue that expresses CD8 comprising administering a radiolabeled anti-CD8 antibody conjugate of the present disclosure to the tissue; and visualizing the CD8 expression by positron emission tomography (PET) imaging. In one embodiment, the tissue is comprised in a tumor. In one embodiment, the tissue is comprised in a tumor cell culture or tumor cell line. In one embodiment, the tissue is comprised in a tumor lesion in a subject. In one embodiment, the tissue is intratumoral lymphocytes in a tissue. In one embodiment, the tissue comprises CD8-expressing cells (paragraph 0204).
According to one aspect, the disclosure provides methods for predicting a response to anti-tumor therapy. The method comprises administering radiolabeled anti-CD8 antibody conjugate to a subject in need thereof, and determining that the subject's solid tumor comprises CD8 positive T cells. If the subject's tumors are infiltrated with CD8 positive T cells, or immunologically ‘hot,’ the subject will likely respond to anti-tumor therapy. The presence of CD8 positive T cells can be a predictive marker of response or a prognostic marker for survival. For example, baseline tumor infiltration with CD8 positive cells is prognostic of survival in breast, head/neck, and ovarian cancer. In addition, tumor infiltration of CD8 positive cells detected during anti-PD-1 therapy or anti-PDL-1 therapy is a predictive marker of response to treatment (paragraph 0207).
According to one aspect, the present disclosure provides methods for determining if a subject having a tumor is suitable for anti-tumor therapy, the methods comprising administering a radiolabeled antibody conjugate of the present disclosure, and localizing the administered radiolabeled antibody conjugate in the tumor by PET imaging wherein presence of the radiolabeled antibody conjugate in the tumor identifies the subject as suitable for anti-tumor therapy (paragraph 0208).
In some embodiments, the conjugate is chelated with a positron emitter in an amount sufficient to provide a specific activity suitable for clinical PET imaging. In some embodiments, the amount of chelated positron emitter is an amount sufficient to provide a specific activity of about 1 to about 50 mCi per 1-50 mg of the protein that binds CD8. In some embodiments, the amount of chelated positron emitter is an amount sufficient to provide a specific activity of up to 50 mCi… or about 5 to about 10 mCi (paragraph 0188-9).
As used herein, the expression “a subject in need thereof” means a human or non-human mammal that exhibits one or more symptoms or indications of cancer, and/or who has been diagnosed with cancer, including a solid tumor and who needs treatment for the same. The expression includes subjects with primary or established tumors. In specific embodiments, the expression includes human subjects that have and/or need treatment for a solid tumor, e.g., colon cancer, breast cancer, lung cancer, prostate cancer, skin cancer, liver cancer, bone cancer, ovarian cancer, cervical cancer, pancreatic cancer, head and neck cancer, and brain cancer (paragraph 0219).
In certain embodiments, the radiolabeled anti-CD8 conjugate can be administered at a dose of about 0.1 mg/kg of body weight to about 100 mg/kg of body weight of the subject, for example, about 0.1 mg/kg to about 50 mg/kg, or about 0.5 mg/kg to about 25 mg/kg, or about 0.1 mg/kg to about 1.0 mg/kg of body weight (paragraph 0241).
To determine whether there is efficacy in anti-tumor therapy, the uptake of the radiolabeled conjugate is quantified at baseline and at one or more time points after administration of the CD8 inhibitor. For example, the uptake of the administered radiolabeled antibody conjugate (e.g., radiolabeled anti-CD8 antibody conjugate) may be measured at day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 14, day 15, day 22, day 25, day 29, day 36, day 43, day 50, day 57, day 64, day 71, day 85; or at the end of week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24, or longer, after the initial treatment with the PD-1/PD-L1 signaling axis (e.g., an anti-PD-1 antibody). The difference between the value of the uptake at a particular time point following initiation of treatment and the value of the uptake at baseline is used to establish whether anti-tumor therapy is efficacious (tumor regression or progression) (paragraph 0239).
In certain embodiments, the imaging is carried out 1, 2, 3, 4, 5, 6 or 7 days after administration of the radiolabeled conjugate. In certain embodiments, the imaging is carried out on the same day upon administration of the radiolabeled antibody conjugate (i.e. within 36 hours as claimed).
See also claims 43-46 which recite a method for monitoring T-cell presence in a tumor over time, the method comprising: (a) administering a radiolabeled anti-CD8 antibody conjugate at a first timepoint to a subject having the tumor and determining the presence of CD8 positive T-cells in the tumor; (b) administering one or more doses of an anti-tumor therapy to the subject; and (c) administering a radiolabeled anti-CD8 antibody conjugate at a second timepoint to the subject 1 to 20 weeks after administration of the anti-tumor therapy and determining the presence of CD8 positive T-cells in the tumor; wherein the presence of T-cells in the tumor indicates a positive response to the anti-tumor therapy; and wherein step (c) is repeated over the course of treatment with the anti-tumor therapy; and wherein the first timepoint occurs prior to (b); and wherein the CD8 positive T-cells according to (a) are compared relative to the CD8 positive T-cells according to (c) and an increase in CD8 positive T-cells over time indicates a positive response to the anti-tumor therapy.
Giurleo further teaches other engineered molecules, such as domain-specific antibodies… diabodies, …minibodies (paragraph 0147).
Giurleo does not specifically recite wherein a radiolabeled anti-CD8 construct providing a radiation activity of about 0.5 to 3.6 mCi; and about 10 mg or less of the antigen-binding construct is administered to a human subject.
Bryans teaches that dosages are based on an average human subject having a weight of about 60 kg to 70 kg (paragraph 0203).
It would have been obvious to one of ordinary skill in the art at the time of the invention to optimize the dosage of radiolabeled anti-CD8 construct for monitoring the efficacy of anti-tumor therapy over time in a human subject by monitoring T-cell presence in a tumor over time before and after administering a radiolabeled anti-CD8 antibody conjugate after administration of the anti-tumor therapy and comparing images, including indication of tumor response to the anti-tumor therapy and performing monitoring over time over the course of therapy. One of ordinary skill in the art would have been motivated to select of an amount of 10 mg or less of radiolabeled anti-CD8 construct, as Giurleo teaches the radiolabeled anti-CD8 conjugate can be administered at a dose of about 0.1 mg/kg to about 1.0 mg/kg of body weight (paragraph 0241), and Bryans teaches that dosages are based on an average human subject having a weight of about 60 kg to 70 kg. Accordingly, administration of 0.1 mg/kg to a 60 kg human corresponds to about 6.0 mg. Giurleo teaches the amount of of chelated positron emitter is an amount sufficient to provide a specific activity of about 1 to about 50 mCi per 1-50 mg, or about 5 to about 10 mCi (paragraph 0189). Accordingly, one of ordinary skill in the art would have been capable of selection of a radiolabeled anti-CD8 construct in the claimed amount and having the claimed radiation activity of about 3.5 mCi with a reasonable expectation of success. Furthermore the claims differ from the reference by reciting a dosage amount of the active component. However, the administration of various pharmaceutical compositions provided at varying amount of active agent is within the level of skill of one having ordinary skill in the art at the time of the invention. It has also been held that the mere selection of proportions and ranges is not patentable absent a showing of criticality. See In re Russell, 439 F.2d 1228 169 USPQ 426 (CCPA 1971).
Claim(s) 2-5, 7, 9, 11, 17, 20, 23, 24, 26 and 50-55 are rejected under 35 U.S.C. 103 as being unpatentable over Pandit-Taskar (J. Nucl. Med., May 2018, 59 (Suppl. 1), 596) in view of Giurleo et al. (US 2019/0023790).
Pandit-Taskar teaches that tumor infiltrating CD 8 positive T lymphocytes play a central role in the anti-tumor immune response. Non Invasive imaging of CD8 T cells can provide new insights in the mechanisms of immunotherapy and potentially predict treatment responses. We are therefore studying the safety and feasibility of PET/CT imaging with a radiolabeled minibody (Mb) against CD8 (89Zr-Df-IAB22M2C) for imaging CD8 positive T cells in patients undergoing immunotherapy.
In an ongoing prospective study 2 pts (1 melanoma, 1 hepatocellular carcinoma) received 3 mCi of 89Zr-Df-IAB22M2C of radiolabeled Mb (0.2 and 0.5mg of Mb) followed by PET/CT scans at ~1-2 h, 6-8 24, 48 h and 120—144 h post injection (PI). Serum samples and whole body (WB) counts were obtained at each imaging time point. All patients were monitored for vitals and side effects during and after the infusion up to the last time point of imaging. Biodistribution and uptake in normal organs, lymph nodes and tumor lesions was evaluated.
89Zr-Df-IAB22M2C infusion was tolerated well and no immediate or delayed side effects were seen in either pt after injection. Activity in the serum cleared exceptionally rapidly for an antibody fragment, reaching an average of 5.7 %ID/l at 30 min post-injection and generally conformed to a bi-exponential function with respective partition coefficients; Tbiol of 10%ID/l; 0.9h and 1.5%ID/l; 152h. Prominent uptake was seen in multiple normal lymph nodes as early as 2 h pi reaching peak levels by 24- 48 h pi. Maximum nodal uptake ranged from 4.0- 34.9 at 48 h pi. Spleen, bone marrow and liver also showed tracer uptake with SUVMAX of 115, 18.1 and 6.1, respectively. Renal uptake was relatively low and primarily in cortex with SUVmax of 7.2 at 24-48 h. Uptake in tumor lesions was seen in both patients, as early as 2 h imaging. The majority of lesions were seen by 24 h and maximum uptake in lesions was seen at 48 h in most sites Maximum lesion uptake, evaluated in 6 target lesions including 1 lesion in muscle, two liver lesions and 3 nodes ranged between 5.85- 22.8. While physiologic uptake was seen in liver in both patients, the HCC showed prominent uptake and was visualized with high contrast on PET/CT imaging (Figure). Preliminary data from this ongoing study shows that 89Zr-Df-IAB22M2C imaging is safe, has favorable biodistribution and kinetics with possible detection of lesions at 24 - 48 h p.i.
Pandi-Taskar does specifically teach treating a patient comprising administering to a human patient diagnosed with a cancer a first dose of radiolabeled anti-CD8 construct, detecting the labeled antigen-binding construct in the patient at a first time point after administering the first dose, to generate a first patient image corresponding to the first time point, determining a first abundance and/or distribution of CD8 cells in one or more tissues and/or neoplasia in the patient based on the first patient image; administering to the patient a first treatment for the cancer after administering the first dose, wherein the first treatment comprises an immunotherapy; after administering the first treatment, administering to the human patient diagnosed with the cancer a second dose of the antigen-binding construct; determining a second abundance and/or distribution of CD8 cells in the one or more tissues and/or neoplasia in the patient based on a second patient image; comparing the first patient image to the second patient image to determine if the tissue and/or neoplasia demonstrates increased CD8 infiltration, wherein increased CD8 infiltration indicates that the first treatment is effective against the cancer; and administering to the patient a second treatment for the cancer based at least on the comparison of the first and second patient images, wherein the second treatment comprises a second immunotherapy.
Giurleo teaches methods for monitoring the efficacy of an anti-tumor therapy in a subject, wherein the methods comprise selecting a subject with a solid tumor wherein the subject is being treated with an anti-tumor therapy; administering a radiolabeled anti-CD8 conjugate described herein to the subject; imaging the localization of the administered radiolabeled conjugate in the tumor by PET imaging; and determining tumor growth, wherein a decrease from the baseline in uptake of the conjugate or radiolabeled signal indicates efficacy of the anti-tumor therapy. In certain embodiments, the anti-tumor therapy comprises a PD-1 inhibitor (e.g., REGN2810, BGB-A317, nivolumab, pidilizumab, and pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, MDX-1105, and REGN3504, as well as those disclosed in Patent Publication No. US 2015-0203580), CTLA-4 inhibitor (e.g., ipilimumab), a TIM3 inhibitor, a BTLA inhibitor, a TIGIT inhibitor, a CD47 inhibitor, a GITR inhibitor, an antagonist of another T cell co-inhibitor or ligand (e.g., an antibody to LAG3, CD-28, 2B4, LY108, LAIR1, ICOS, CD160 or VISTA), an indoleamine-2,3-dioxygenase (IDO) inhibitor, a vascular endothelial growth factor (VEGF) antagonist [e.g., a “VEGF-Trap” such as aflibercept or other VEGF-inhibiting fusion protein as set forth in U.S. Pat. No. 7,087,411, or an anti-VEGF antibody or antigen-binding fragment thereof (e.g., bevacizumab, or ranibizumab) or a small molecule kinase inhibitor of VEGF receptor (e.g., sunitinib, sorafenib, or pazopanib)], an Ang2 inhibitor (e.g., nesvacumab), a transforming growth factor beta (TGFβ) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor (e.g., erlotinib, cetuximab), a CD20 inhibitor (e.g., an anti-CD20 antibody such as rituximab), an antibody to a tumor-specific antigen [e.g., CA9, CA125, melanoma-associated antigen 3 (MAGE3), carcinoembryonic antigen (CEA), vimentin, tumor-M2-PK, prostate-specific antigen (PSA), mucin-1, MART-1, and CA19-9], a vaccine (e.g., Bacillus Calmette-Guerin, a cancer vaccine), an adjuvant to increase antigen presentation (e.g., granulocyte-macrophage colony-stimulating factor), a bispecific antibody (e.g., CD3×CD20 bispecific antibody, or PSMA×CD3 bispecific antibody), a cytotoxin, a chemotherapeutic agent (e.g., dacarbazine, temozolomide, cyclophosphamide, docetaxel, doxorubicin, daunorubicin, cisplatin, carboplatin, gemcitabine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, and vincristine), cyclophosphamide, radiotherapy, an IL-6R inhibitor (e.g., sarilumab), an IL-4R inhibitor (e.g., dupilumab), an IL-10 inhibitor, a cytokine such as IL-2, IL-7, IL-21, and IL-15, and an antibody-drug conjugate (ADC) (e.g., anti-CD19-DM4 ADC, and anti-DS6-DM4 ADC) (paragraph 0039).
Exemplary anti-CD8 antibodies are listed in Table 1, which provides the amino acid sequence identifiers and nucleic acid sequence identifiers of the heavy and light chain complementarity determining region sequences and heavy and light chain variable region sequences (paragraph 0011).
Provided are methods for predicting response of a subject to an anti-tumor therapy, the methods comprising selecting a subject with a solid tumor; and determining if the tumor is CD8 positive, wherein if the tumor is CD8 positive it predicts a positive response of the subject to an anti-tumor therapy. In certain embodiments, the tumor is determined positive by administering a radiolabeled anti-CD8 antibody conjugate of the present disclosure and localizing the radiolabeled antibody conjugate in the tumor by PET imaging wherein presence of the radiolabeled antibody conjugate in the tumor indicates that the tumor is CD8 positive. In some embodiments, the anti-tumor therapy is selected from a PD-1 inhibitor (e.g., REGN2810, BGB-A317, nivolumab, pidilizumab, and pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, MDX-1105, and REGN3504), CTLA-4 inhibitor (e.g., ipilimumab), … etc (paragraph 0040).
Provided are methods of imaging a tissue comprising CD8-expressing cells, for example, CD8-expressing intratumoral lymphocytes, or CD8 positive T cells, the methods comprising administering a radiolabeled anti-CD8 antibody conjugate described herein to the tissue, and visualizing the CD8 expression by PET imaging (paragraph 0034).
Provided are methods for predicting a positive response to an anti-tumor therapy in a subject with a solid tumor. The methods comprise administering a radiolabeled anti-CD8 antibody conjugate to the subject to determine the presence of CD8 positive cells in the solid tumor; wherein the presence of CD8 positive cells predicts a positive response to an anti-tumor therapy (paragraph 0041).
Provided are methods for monitoring a positive response to an anti-tumor therapy in a subject with a solid tumor. The methods comprise (a) administering one or more doses of an anti-tumor therapy to the subject; and (b) administering a radiolabeled anti-CD8 antibody conjugate to the subject 1 to 20 weeks after administration of the anti-tumor therapy to determine the presence of CD8 positive cells in the solid tumor. The presence of CD8 positive cells indicates a positive response to the anti-tumor therapy (paragraph 0042).
Provided are methods for predicting or monitoring success or efficacy of anti-tumor therapy in a subject with a solid tumor, the method comprising: (a) determining the level of CD8 positive cells in the tumor; and (b) correlating the level of CD8 positive cells with successful anti-tumor therapy. An elevated level of CD8 above a certain threshold is predictive or indicative of successful anti-tumor therapy (paragraph 0043).
Provided are methods for monitoring T-cell presence or T-cell infiltration in a tumor over time, the method comprising: (a) administering a radiolabeled anti-CD8 antibody conjugate at a first timepoint to a subject having the tumor and determining the presence of CD8 positive T-cells in the tumor; (b) administering one or more doses of an anti-tumor therapy to the subject; and (c) administering a radiolabeled anti-CD8 antibody conjugate at a second timepoint to the subject 1 to 20 weeks after administration of the anti-tumor therapy and determining the presence of CD8 positive T-cells in the tumor. The presence of T-cells in the tumor is indicative of a positive response to the anti-tumor therapy (paragraph 0044).
Suitable positron emitters include, but are not limited to, those that form stable complexes with the chelating moiety and have physical half-lives suitable for immuno-PET imaging purposes. Illustrative positron emitters include, but are not limited to 89Zr, 68Ga, 64Cu, 44Sc, and 86Y. Suitable positron emitters also include those that directly bond with the CD8 binding protein, including, but not limited to 76Br and 124I (paragraph 0161).
According to one aspect, the present disclosure provides methods of imaging a tissue that expresses CD8 comprising administering a radiolabeled anti-CD8 antibody conjugate of the present disclosure to the tissue; and visualizing the CD8 expression by positron emission tomography (PET) imaging. In one embodiment, the tissue is comprised in a tumor. In one embodiment, the tissue is comprised in a tumor cell culture or tumor cell line. In one embodiment, the tissue is comprised in a tumor lesion in a subject. In one embodiment, the tissue is intratumoral lymphocytes in a tissue. In one embodiment, the tissue comprises CD8-expressing cells (paragraph 0204).
According to one aspect, the disclosure provides methods for predicting a response to anti-tumor therapy. The method comprises administering radiolabeled anti-CD8 antibody conjugate to a subject in need thereof, and determining that the subject's solid tumor comprises CD8 positive T cells. If the subject's tumors are infiltrated with CD8 positive T cells, or immunologically ‘hot,’ the subject will likely respond to anti-tumor therapy. The presence of CD8 positive T cells can be a predictive marker of response or a prognostic marker for survival. For example, baseline tumor infiltration with CD8 positive cells is prognostic of survival in breast, head/neck, and ovarian cancer. In addition, tumor infiltration of CD8 positive cells detected during anti-PD-1 therapy or anti-PDL-1 therapy is a predictive marker of response to treatment (paragraph 0207).
According to one aspect, the present disclosure provides methods for determining if a subject having a tumor is suitable for anti-tumor therapy, the methods comprising administering a radiolabeled antibody conjugate of the present disclosure, and localizing the administered radiolabeled antibody conjugate in the tumor by PET imaging wherein presence of the radiolabeled antibody conjugate in the tumor identifies the subject as suitable for anti-tumor therapy (paragraph 0208).
In some embodiments, the conjugate is chelated with a positron emitter in an amount sufficient to provide a specific activity suitable for clinical PET imaging. In some embodiments, the amount of chelated positron emitter is an amount sufficient to provide a specific activity of about 1 to about 50 mCi per 1-50 mg of the protein that binds CD8. In some embodiments, the amount of chelated positron emitter is an amount sufficient to provide a specific activity of up to 50 mCi… or about 5 to about 10 mCi (paragraph 0188-9).
As used herein, the expression “a subject in need thereof” means a human or non-human mammal that exhibits one or more symptoms or indications of cancer, and/or who has been diagnosed with cancer, including a solid tumor and who needs treatment for the same. The expression includes subjects with primary or established tumors. In specific embodiments, the expression includes human subjects that have and/or need treatment for a solid tumor, e.g., colon cancer, breast cancer, lung cancer, prostate cancer, skin cancer, liver cancer, bone cancer, ovarian cancer, cervical cancer, pancreatic cancer, head and neck cancer, and brain cancer (paragraph 0219).
In certain embodiments, the radiolabeled anti-CD8 conjugate can be administered at a dose of about 0.1 mg/kg of body weight to about 100 mg/kg of body weight of the subject, for example, about 0.1 mg/kg to about 50 mg/kg, or about 0.5 mg/kg to about 25 mg/kg, or about 0.1 mg/kg to about 1.0 mg/kg of body weight (paragraph 0241).
To determine whether there is efficacy in anti-tumor therapy, the uptake of the radiolabeled conjugate is quantified at baseline and at one or more time points after administration of the CD8 inhibitor. For example, the uptake of the administered radiolabeled antibody conjugate (e.g., radiolabeled anti-CD8 antibody conjugate) may be measured at day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 14, day 15, day 22, day 25, day 29, day 36, day 43, day 50, day 57, day 64, day 71, day 85; or at the end of week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24, or longer, after the initial treatment with the PD-1/PD-L1 signaling axis (e.g., an anti-PD-1 antibody). The difference between the value of the uptake at a particular time point following initiation of treatment and the value of the uptake at baseline is used to establish whether anti-tumor therapy is efficacious (tumor regression or progression) (paragraph 0239).
In certain embodiments, the imaging is carried out 1, 2, 3, 4, 5, 6 or 7 days after administration of the radiolabeled conjugate. In certain embodiments, the imaging is carried out on the same day upon administration of the radiolabeled antibody conjugate (i.e. within 36 hours as claimed).
See also claims 43-46 which recite a method for monitoring T-cell presence in a tumor over time, the method comprising: (a) administering a radiolabeled anti-CD8 antibody conjugate at a first timepoint to a subject having the tumor and determining the presence of CD8 positive T-cells in the tumor; (b) administering one or more doses of an anti-tumor therapy to the subject; and (c) administering a radiolabeled anti-CD8 antibody conjugate at a second timepoint to the subject 1 to 20 weeks after administration of the anti-tumor therapy and determining the presence of CD8 positive T-cells in the tumor; wherein the presence of T-cells in the tumor indicates a positive response to the anti-tumor therapy; and wherein step (c) is repeated over the course of treatment with the anti-tumor therapy; and wherein the first timepoint occurs prior to (b); and wherein the CD8 positive T-cells according to (a) are compared relative to the CD8 positive T-cells according to (c) and an increase in CD8 positive T-cells over time indicates a positive response to the anti-tumor therapy.
Giurleo further teaches other engineered molecules, such as domain-specific antibodies… diabodies, …minibodies (paragraph 0147).
It would have been obvious to one of ordinary skill in the art at the time of the invention to perform treatment of a human patient upon administration of a radiolabeled anti-CD8 construct within the claimed range prior to and after treatment with anti-tumor therapy for comparison of images and determination of treatment efficacy when Pandit-Taskar is taken in view of Giurleo. Pandit-Taskar teaches administration of the claimed dosage of 89Zr-Df-IAB22M2C for imaging of tumor and detection of CD8+ expressing T cells. One would have been motivated to further administer an anti-tumor therapy for evaluation and monitoring of treatment efficacy because Giurleo teaches methods for monitoring the efficacy of an anti-tumor therapy in a subject, wherein the methods comprise selecting a subject with a solid tumor wherein the subject is being treated with an anti-tumor therapy; administering a radiolabeled anti-CD8 conjugate described herein to the subject; imaging the localization of the administered radiolabeled conjugate in the tumor by PET imaging; and determining tumor growth, wherein a decrease from the baseline in uptake of the conjugate or radiolabeled signal indicates efficacy of the anti-tumor therapy, including monitoring treatment and evaluation over time.
Claim(s) 2-5, 7, 9, 11, 17, 20, 23, 24, 26 and 50-55 are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trials.gov ID NCT03107663, ⁸⁹Zr-Df-IAB22M2C PET/CT in Patients With Selected Solid Malignancies or Hodgkin's Lymphoma, as published online 08-02-2017) in view of in view of Giurleo et al. (US 2019/0023790).
Clinical Trials teaches a phase I study of positron emission tomography (PET/CT) with 89Zr-Df-IAB22M2C in patients with Selected, Metastatic Solid Malignancies (Non Small Cell Lung Cancer (NSCLC), Small Cell Lung Cancer (SCLC), Squamous Cell Carcinoma Head and Neck (SqCCHN), Melanoma, Merkel Cell Tumor, Renal, Bladder, Hepatocellular, Triple Negative Breast, or Hodgkin's Lymphoma. Up to 24 subjects are planned to be enrolled in this clinical study.
This phase 1 study is a dose escalation study of 89Zr-Df-IAB22M2C to evaluate safety, tolerability, optimal time point and protein dose for imaging, biodistribution, radiation dosimetry, as well as the ability of 89Zr-Df-IAB22M2C to detect CD8+ expressing T cells. The investigational imaging agent to be administered in this study will be 3.0 (±20%) mCi dose of 89Zr-Df- IAB22M2C injected intravenously. Four cohorts of up to 6 patients each will be studied sequentially with dose escalation at 0.2 mg, 0.5 mg, 1.0 mg, and 1.5 mg total protein doses followed by an expansion cohort at the optimal dose.
Clinical Trials does specifically teach treating a patient comprising administering to a human patient diagnosed with a cancer a first dose of radiolabeled anti-CD8 construct, detecting the labeled antigen-binding construct in the patient at a first time point after administering the first dose, to generate a first patient image corresponding to the first time point, determining a first abundance and/or distribution of CD8 cells in one or more tissues and/or neoplasia in the patient based on the first patient image; administering to the patient a first treatment for the cancer after administering the first dose, wherein the first treatment comprises an immunotherapy; after administering the first treatment, administering to the human patient diagnosed with the cancer a second dose of the antigen-binding construct; determining a second abundance and/or distribution of CD8 cells in the one or more tissues and/or neoplasia in the patient based on a second patient image; comparing the first patient image to the second patient image to determine if the tissue and/or neoplasia demonstrates increased CD8 infiltration, wherein increased CD8 infiltration indicates that the first treatment is effective against the cancer; and administering to the patient a second treatment for the cancer based at least on the comparison of the first and second patient images, wherein the second treatment comprises a second immunotherapy.
Giurleo teaches methods for monitoring the efficacy of an anti-tumor therapy in a subject, wherein the methods comprise selecting a subject with a solid tumor wherein the subject is being treated with an anti-tumor therapy; administering a radiolabeled anti-CD8 conjugate described herein to the subject; imaging the localization of the administered radiolabeled conjugate in the tumor by PET imaging; and determining tumor growth, wherein a decrease from the baseline in uptake of the conjugate or radiolabeled signal indicates efficacy of the anti-tumor therapy. In certain embodiments, the anti-tumor therapy comprises a PD-1 inhibitor (e.g., REGN2810, BGB-A317, nivolumab, pidilizumab, and pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, MDX-1105, and REGN3504, as well as those disclosed in Patent Publication No. US 2015-0203580), CTLA-4 inhibitor (e.g., ipilimumab), a TIM3 inhibitor, a BTLA inhibitor, a TIGIT inhibitor, a CD47 inhibitor, a GITR inhibitor, an antagonist of another T cell co-inhibitor or ligand (e.g., an antibody to LAG3, CD-28, 2B4, LY108, LAIR1, ICOS, CD160 or VISTA), an indoleamine-2,3-dioxygenase (IDO) inhibitor, a vascular endothelial growth factor (VEGF) antagonist [e.g., a “VEGF-Trap” such as aflibercept or other VEGF-inhibiting fusion protein as set forth in U.S. Pat. No. 7,087,411, or an anti-VEGF antibody or antigen-binding fragment thereof (e.g., bevacizumab, or ranibizumab) or a small molecule kinase inhibitor of VEGF receptor (e.g., sunitinib, sorafenib, or pazopanib)], an Ang2 inhibitor (e.g., nesvacumab), a transforming growth factor beta (TGFβ) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor (e.g., erlotinib, cetuximab), a CD20 inhibitor (e.g., an anti-CD20 antibody such as rituximab), an antibody to a tumor-specific antigen [e.g., CA9, CA125, melanoma-associated antigen 3 (MAGE3), carcinoembryonic antigen (CEA), vimentin, tumor-M2-PK, prostate-specific antigen (PSA), mucin-1, MART-1, and CA19-9], a vaccine (e.g., Bacillus Calmette-Guerin, a cancer vaccine), an adjuvant to increase antigen presentation (e.g., granulocyte-macrophage colony-stimulating factor), a bispecific antibody (e.g., CD3×CD20 bispecific antibody, or PSMA×CD3 bispecific antibody), a cytotoxin, a chemotherapeutic agent (e.g., dacarbazine, temozolomide, cyclophosphamide, docetaxel, doxorubicin, daunorubicin, cisplatin, carboplatin, gemcitabine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, and vincristine), cyclophosphamide, radiotherapy, an IL-6R inhibitor (e.g., sarilumab), an IL-4R inhibitor (e.g., dupilumab), an IL-10 inhibitor, a cytokine such as IL-2, IL-7, IL-21, and IL-15, and an antibody-drug conjugate (ADC) (e.g., anti-CD19-DM4 ADC, and anti-DS6-DM4 ADC) (paragraph 0039).
Exemplary anti-CD8 antibodies are listed in Table 1, which provides the amino acid sequence identifiers and nucleic acid sequence identifiers of the heavy and light chain complementarity determining region sequences and heavy and light chain variable region sequences (paragraph 0011).
Provided are methods for predicting response of a subject to an anti-tumor therapy, the methods comprising selecting a subject with a solid tumor; and determining if the tumor is CD8 positive, wherein if the tumor is CD8 positive it predicts a positive response of the subject to an anti-tumor therapy. In certain embodiments, the tumor is determined positive by administering a radiolabeled anti-CD8 antibody conjugate of the present disclosure and localizing the radiolabeled antibody conjugate in the tumor by PET imaging wherein presence of the radiolabeled antibody conjugate in the tumor indicates that the tumor is CD8 positive. In some embodiments, the anti-tumor therapy is selected from a PD-1 inhibitor (e.g., REGN2810, BGB-A317, nivolumab, pidilizumab, and pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, durvalumab, MDX-1105, and REGN3504), CTLA-4 inhibitor (e.g., ipilimumab), … etc (paragraph 0040).
Provided are methods of imaging a tissue comprising CD8-expressing cells, for example, CD8-expressing intratumoral lymphocytes, or CD8 positive T cells, the methods comprising administering a radiolabeled anti-CD8 antibody conjugate described herein to the tissue, and visualizing the CD8 expression by PET imaging (paragraph 0034).
Provided are methods for predicting a positive response to an anti-tumor therapy in a subject with a solid tumor. The methods comprise administering a radiolabeled anti-CD8 antibody conjugate to the subject to determine the presence of CD8 positive cells in the solid tumor; wherein the presence of CD8 positive cells predicts a positive response to an anti-tumor therapy (paragraph 0041).
Provided are methods for monitoring a positive response to an anti-tumor therapy in a subject with a solid tumor. The methods comprise (a) administering one or more doses of an anti-tumor therapy to the subject; and (b) administering a radiolabeled anti-CD8 antibody conjugate to the subject 1 to 20 weeks after administration of the anti-tumor therapy to determine the presence of CD8 positive cells in the solid tumor. The presence of CD8 positive cells indicates a positive response to the anti-tumor therapy (paragraph 0042).
Provided are methods for predicting or monitoring success or efficacy of anti-tumor therapy in a subject with a solid tumor, the method comprising: (a) determining the level of CD8 positive cells in the tumor; and (b) correlating the level of CD8 positive cells with successful anti-tumor therapy. An elevated level of CD8 above a certain threshold is predictive or indicative of successful anti-tumor therapy (paragraph 0043).
Provided are methods for monitoring T-cell presence or T-cell infiltration in a tumor over time, the method comprising: (a) administering a radiolabeled anti-CD8 antibody conjugate at a first timepoint to a subject having the tumor and determining the presence of CD8 positive T-cells in the tumor; (b) administering one or more doses of an anti-tumor therapy to the subject; and (c) administering a radiolabeled anti-CD8 antibody conjugate at a second timepoint to the subject 1 to 20 weeks after administration of the anti-tumor therapy and determining the presence of CD8 positive T-cells in the tumor. The presence of T-cells in the tumor is indicative of a positive response to the anti-tumor therapy (paragraph 0044).
Suitable positron emitters include, but are not limited to, those that form stable complexes with the chelating moiety and have physical half-lives suitable for immuno-PET imaging purposes. Illustrative positron emitters include, but are not limited to 89Zr, 68Ga, 64Cu, 44Sc, and 86Y. Suitable positron emitters also include those that directly bond with the CD8 binding protein, including, but not limited to 76Br and 124I (paragraph 0161).
According to one aspect, the present disclosure provides methods of imaging a tissue that expresses CD8 comprising administering a radiolabeled anti-CD8 antibody conjugate of the present disclosure to the tissue; and visualizing the CD8 expression by positron emission tomography (PET) imaging. In one embodiment, the tissue is comprised in a tumor. In one embodiment, the tissue is comprised in a tumor cell culture or tumor cell line. In one embodiment, the tissue is comprised in a tumor lesion in a subject. In one embodiment, the tissue is intratumoral lymphocytes in a tissue. In one embodiment, the tissue comprises CD8-expressing cells (paragraph 0204).
According to one aspect, the disclosure provides methods for predicting a response to anti-tumor therapy. The method comprises administering radiolabeled anti-CD8 antibody conjugate to a subject in need thereof, and determining that the subject's solid tumor comprises CD8 positive T cells. If the subject's tumors are infiltrated with CD8 positive T cells, or immunologically ‘hot,’ the subject will likely respond to anti-tumor therapy. The presence of CD8 positive T cells can be a predictive marker of response or a prognostic marker for survival. For example, baseline tumor infiltration with CD8 positive cells is prognostic of survival in breast, head/neck, and ovarian cancer. In addition, tumor infiltration of CD8 positive cells detected during anti-PD-1 therapy or anti-PDL-1 therapy is a predictive marker of response to treatment (paragraph 0207).
According to one aspect, the present disclosure provides methods for determining if a subject having a tumor is suitable for anti-tumor therapy, the methods comprising administering a radiolabeled antibody conjugate of the present disclosure, and localizing the administered radiolabeled antibody conjugate in the tumor by PET imaging wherein presence of the radiolabeled antibody conjugate in the tumor identifies the subject as suitable for anti-tumor therapy (paragraph 0208).
In some embodiments, the conjugate is chelated with a positron emitter in an amount sufficient to provide a specific activity suitable for clinical PET imaging. In some embodiments, the amount of chelated positron emitter is an amount sufficient to provide a specific activity of about 1 to about 50 mCi per 1-50 mg of the protein that binds CD8. In some embodiments, the amount of chelated positron emitter is an amount sufficient to provide a specific activity of up to 50 mCi… or about 5 to about 10 mCi (paragraph 0188-9).
As used herein, the expression “a subject in need thereof” means a human or non-human mammal that exhibits one or more symptoms or indications of cancer, and/or who has been diagnosed with cancer, including a solid tumor and who needs treatment for the same. The expression includes subjects with primary or established tumors. In specific embodiments, the expression includes human subjects that have and/or need treatment for a solid tumor, e.g., colon cancer, breast cancer, lung cancer, prostate cancer, skin cancer, liver cancer, bone cancer, ovarian cancer, cervical cancer, pancreatic cancer, head and neck cancer, and brain cancer (paragraph 0219).
In certain embodiments, the radiolabeled anti-CD8 conjugate can be administered at a dose of about 0.1 mg/kg of body weight to about 100 mg/kg of body weight of the subject, for example, about 0.1 mg/kg to about 50 mg/kg, or about 0.5 mg/kg to about 25 mg/kg, or about 0.1 mg/kg to about 1.0 mg/kg of body weight (paragraph 0241).
To determine whether there is efficacy in anti-tumor therapy, the uptake of the radiolabeled conjugate is quantified at baseline and at one or more time points after administration of the CD8 inhibitor. For example, the uptake of the administered radiolabeled antibody conjugate (e.g., radiolabeled anti-CD8 antibody conjugate) may be measured at day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 14, day 15, day 22, day 25, day 29, day 36, day 43, day 50, day 57, day 64, day 71, day 85; or at the end of week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24, or longer, after the initial treatment with the PD-1/PD-L1 signaling axis (e.g., an anti-PD-1 antibody). The difference between the value of the uptake at a particular time point following initiation of treatment and the value of the uptake at baseline is used to establish whether anti-tumor therapy is efficacious (tumor regression or progression) (paragraph 0239).
In certain embodiments, the imaging is carried out 1, 2, 3, 4, 5, 6 or 7 days after administration of the radiolabeled conjugate. In certain embodiments, the imaging is carried out on the same day upon administration of the radiolabeled antibody conjugate (i.e. within 36 hours as claimed).
See also claims 43-46 which recite a method for monitoring T-cell presence in a tumor over time, the method comprising: (a) administering a radiolabeled anti-CD8 antibody conjugate at a first timepoint to a subject having the tumor and determining the presence of CD8 positive T-cells in the tumor; (b) administering one or more doses of an anti-tumor therapy to the subject; and (c) administering a radiolabeled anti-CD8 antibody conjugate at a second timepoint to the subject 1 to 20 weeks after administration of the anti-tumor therapy and determining the presence of CD8 positive T-cells in the tumor; wherein the presence of T-cells in the tumor indicates a positive response to the anti-tumor therapy; and wherein step (c) is repeated over the course of treatment with the anti-tumor therapy; and wherein the first timepoint occurs prior to (b); and wherein the CD8 positive T-cells according to (a) are compared relative to the CD8 positive T-cells according to (c) and an increase in CD8 positive T-cells over time indicates a positive response to the anti-tumor therapy.
Giurleo further teaches other engineered molecules, such as domain-specific antibodies… diabodies, …minibodies (paragraph 0147).
It would have been obvious to one of ordinary skill in the art at the time of the invention to perform treatment of a human patient upon administration of a radiolabeled anti-CD8 construct within the claimed range prior to and after treatment with anti-tumor therapy for comparison of images and determination of treatment efficacy when Clinical Trials is taken in view of Giurleo. Clinical Trials teaches administration of the claimed dosage of 89Zr-Df-IAB22M2C for imaging of tumor and detection of CD8+ expressing T cells. One would have been motivated to further administer an anti-tumor therapy for evaluation and monitoring of treatment efficacy because Giurleo teaches methods for monitoring the efficacy of an anti-tumor therapy in a subject, wherein the methods comprise selecting a subject with a solid tumor wherein the subject is being treated with an anti-tumor therapy; administering a radiolabeled anti-CD8 conjugate described herein to the subject; imaging the localization of the administered radiolabeled conjugate in the tumor by PET imaging; and determining tumor growth, wherein a decrease from the baseline in uptake of the conjugate or radiolabeled signal indicates efficacy of the anti-tumor therapy, including monitoring treatment and evaluation over time.
Claims 2-5, 7, 9, 11, 17, 20, 23, 24, 26 and 50-55 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (US 2020/0172620).
Chen teaches a method of monitoring treatment progress in a subject having cancer who has or is receiving an immunotherapeutic agent or a cancer vaccine, the method comprising: i) administering the labeled anti-CD8 antibody according to (or as applied to) any of the embodiments above to the subject in conjunction with the immunotherapeutic agent or the cancer vaccine, and ii) detecting binding of the labeled anti-CD8 antibody to CD8+ T cells in the tumor tissue at a first time point and a second time point. In certain embodiments according to (or as applied to) any of the embodiments above, detecting binding of the labeled anti-CD8 antibody to the CD8+ T cells in the tumor tissue in the subject comprises imaging CD8+ T cells in the subject. In certain embodiments according to (or as applied to) any of the embodiments above, imaging the CD8+ T cells in the subject comprises performing a positron emission tomography (PET) scan or positron emission tomography/computed tomography (PET/CT) scan on the subject. In certain embodiments according to (or as applied to) any of the embodiments above, the labeled anti-CD8 antibody is administered before the immunotherapeutic agent or the cancer vaccine, wherein the first time point is after the administration of the labeled anti-CD8 antibody and prior to the administration of the immunotherapeutic agent or the cancer vaccine, and wherein the second time point is after the administration of the immunotherapeutic agent or the cancer vaccine. In certain embodiments according to (or as applied to) any of the embodiments above, the immunotherapeutic agent or the cancer vaccine is administered before the labeled anti-CD8 antibody, wherein the first time point is after the administration of the immunotherapeutic agent or the cancer vaccine and after the administration of the labeled anti-CD8 antibody, and wherein the second time point is after the first time point. In certain embodiments according to (or as applied to) any of the embodiments above, the immunotherapeutic agent is administered to the subject. In certain embodiments according to (or as applied to) any of the embodiments above, the immunotherapeutic agent is an anti-PDL1 antibody, an anti-PD1 antibody, an anti-TIGIT antibody, a TIGIT antagonist, an anti-CSF-1R antibody, an anti-CSF-1R antagonist, an anti-CEA antibody, an anti-CEA antagonist, an anti-CTLA4 antibody, a CTLA4 antagonist, an anti-OX40 antibody, or an OX40 agonist. In certain embodiments according to (or as applied to) any of the embodiments above, the immunotherapeutic agent is an anti-PD-L1 antibody. In certain embodiments according to (or as applied to) any of the embodiments above, the anti-PD-L1 antibody is administered in combination with one or more therapeutic agents. In certain embodiments according to (or as applied to) any of the embodiments above, the one or more therapeutic agents is Tarceva® (erlotinib), Zelboraf® (vemurafenib), Gazyva® (obinutuzumab), Avastin® (bevacizumab), Cotellic® (cobimetinib), Zelboraf® and Cotellic®, Alecensa® (alectinib), Kadcyla® (ado-trastuzumab emtansine), Herceptin® (trastuzumab), Perjeta® (pertuzumab), polatuzumab, INF-alpha, an anti-CD40 agent, an anti-OX40 antibody, an OX40 agonist, an anti-CSF-1R antibody, an anti-CEA antibody, an IDO inhibitor, or an anti-TIGIT antibody. In certain embodiments according to (or as applied to) any of the embodiments above, the immunotherapeutic agent is a bispecific antigen binding molecule that specifically binds CD3. In certain embodiments according to (or as applied to) any of the embodiments above, the bispecific antigen binding molecule is an antibody or an antigen-binding fragment thereof (paragraph 0017).
Methods of monitoring treatment progress are taught. Provided are methods of monitoring treatment progress in a subject having cancer who has previously received or is currently receiving treatment with an immunotherapeutic agent (e.g., an immunotherapeutic agent described elsewhere herein.) Such methods comprise administering a labeled anti-CD8 antibody to the subject in conjunction with the immunotherapeutic agent, and detecting binding of the labeled anti-CD8 antibody to CD8+ T cells in the tumor tissue at a first time point and a second time point. In some embodiments, the labeled anti-CD8 antibody is administered before the immunotherapeutic agent, and the first time point is after the administration of the labeled anti-CD8 antibody and prior to the administration of the immunotherapeutic agent, and the second time point is after the administration of the immunotherapeutic agent. In some embodiments, lower levels of CD8+ T cells in the tumor tissue at the second time point as compared to the first time point indicates positive treatment progress (e.g., beneficial or desired clinical results). In some embodiments, higher levels of CD8+ T cells in the tumor tissue at the second time point as compared to the first time point indicates lack of treatment progress (e.g., lack beneficial or desired clinical results). In some embodiments, the immunotherapeutic agent is administered before the labeled anti-CD8 antibody, the first time point is after the administration of the immunotherapeutic agent and after the administration of the labeled anti-CD8 antibody, and the second time point is after the first time point. In some embodiments, lower levels of CD8+ T cells in the tumor tissue at the second time point as compared to the first time point indicates positive treatment progress (e.g., beneficial or desired clinical results). In some embodiments, higher levels of CD8+ T cells in the tumor tissue at the second time point as compared to the first time point indicates lack of treatment progress (e.g., lack beneficial or desired clinical results). In certain embodiments, the level of CD8+ T cells in the tumor tissue is detected in third, fourth, or fifth subsequent time points. In some embodiments, the time points are at least any one of 1 day, 3 days, 1 week, two weeks, three weeks, four weeks, one month, two months, three months, four months, five months, 6 months, 9 months 12 months, 1.5 years, 2, years, 2.5 years, 3 years or more than three years apart. In certain embodiments, the immunotherapeutic agent is an immune checkpoint inhibitor (paragraph 0215-16).
An anti-CD8 antibody or other CD8 imaging moiety can be used to assess tumor and lymph node infiltration by CD8+ cells. Such imaging is used to identify immune phenotypes that underlie microbiome signatures predictive of patient prognosis and/or response to cancer immunotherapy (paragraph 0276).
In certain embodiments according to (or as applied to) any of the embodiments above, the anti-CD8 antibody is a chimeric antibody, a humanized antibody, or a human antibody. In certain embodiments according to (or as applied to) any of the embodiments above, the anti-CD8 antibody is a monovalent antibody. In certain embodiments according to (or as applied to) any of the embodiments above, the monovalent antibody comprises an antibody heavy chain comprising a first Fc domain, an antibody light chain, and a second Fc domain, wherein the antibody heavy chain pairs with the antibody light chain, and wherein the first Fc domain and the second Fc domain form a dimer. In certain embodiments according to (or as applied to) any of the embodiments above, the first Fc domain comprises a cavity, and wherein the second Fc domain comprises a protuberance which is positionable in the cavity in the first Fc domain (paragraph 0005).
Following the identification of key microbial strains in patients who have CD8+ T cell infiltration to the lymph nodes and/or tumor, a microbiome drug comprising the key microbial strains is made from donor stool obtained from such patients. The microbiome drug is administered to patients who do not demonstrate CD8+ T cell infiltration into the lymph nodes or tumor. Alternatively, a FMT (fecal microbiota transplant) procedure is performed on patients who do not demonstrate CD8+ T cell infiltration into the lymph nodes and/or tumor using donor stool collected from patients who demonstrate CD8+ T cell infiltration to the lymph nodes and/or tumor. In certain embodiments, the FMT or microbiome drug transforms a patient who does not exhibit CD8+ infiltration into the lymph nodes and/or tumor upon cancer immunotherapy into a patient who does respond to cancer immunotherapy (paragraph 0280).
In certain embodiments, CD8 imaging is performed on the patient who does not exhibit CD8+ infiltration into the lymph nodes and/or tumor prior to FMT or prior to administration of the microbiome drug. Following FMT or administration of the microbiome drug, the patient receives immunotherapy. Following immunotherapy, imaging is performed on the patient in order to determine if the FMT or the microbiome drug results in increased CD8+ infiltration into the lymph nodes and/or tumor. In certain embodiments, if increased CD8+ infiltration is observed in response to the cancer immunotherapy treatment after FMT or other microbiome drug, then the FMT or other microbiome drug is considered to have been successful (paragraph 0281).
The CD8 imaging agent used in conjunction with microbiome research and discovery can be any anti-CD8 antibody disclosed herein (e.g., huOKT8v.1, huOKT8v.9, huOKT8v.10, huOKT8v. 11, huOKT8v. 12, huOKT8v. 15, and huOKT8v. 17) (paragraph 0282).
In certain embodiments, the cancer immunotherapy is a checkpoint inhibitor. In certain embodiments, the cancer immunotherapy is a T-cell targeting therapy. In certain embodiments, the T-cell targeting therapy is a T-cell bispecific, trispecific, or multispecific antibody or antigen binding fragment thereof. In certain embodiments, the cancer immunotherapy is a NK cell targeting therapy. In certain embodiments, the NK cell targeting therapy is a bispecific, trispecific, or multispecific antibody or an antigen binding fragment thereof (paragraph 0283).
In certain embodiments, CD8 imaging using an anti-CD8 antibody or other CD8 imaging moiety can be used to assess tumor and lymph node CD8+ infiltration before, during, and after administration of a checkpoint inhibitor or an immune modulating molecule, such as a CD16 or CD3 targeting moiety. Such imaging is used to determine microbiome biomarkers that are associated with efficacy of a checkpoint inhibitor or an immune modulating molecule, such as a CD16 or CD3 targeting moiety (paragraph 0284).
The checkpoint inhibitor as used in this example can be any checkpoint inhibitor. In certain embodiments, the checkpoint inhibitor is an anti-PD1 or an anti-PDL1 antibody. In certain embodiments, the checkpoint inhibitor is atezolizumab (Tecentriq) (paragraph 0285).
Example 9 teaches methods of using CD8 imaging for determining the efficacy of cancer immunotherapies. An anti-CD8 antibody or other CD8 imaging moiety is used to assess tumor and lymph node infiltration by CD8+ cells. Such imaging is used to identify immune phenotypes that are predictive of patient prognosis and/or response to cancer immunotherapy. Such imaging is used to determine the prevalence of CD8+ T-cells in tumors and other lymph nodes, for example. Such imaging is used to select cancer immunotherapy agents or combination cancer agents that include one or more cancer immunotherapy agents.
Predicted pharmacokinetic metrics for huOKT8.v11-OA-LALAPG in humans are provided in Table 13.
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Imaging experiments were performed with 89Zr-huOKT8.v11-OA-LALAPG in a rhesus monkey to determine whether uptake could be detected in tissues that are normally CD8-rich. A rhesus monkey (5 kg) was injected with 10 mg 89Zr-huOKT8.v11-OA-LALAPG containing a 1 mCi radiation dose (paragraph 0265).
Radioactive substances that can be used as detectable labels may be 124I, 64Cu, etc. (paragraph 0166).
The term “antibody” herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, monovalent antibodies (e.g., one-armed antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity, i.e., binding to CD8 (such as a human CD8, a cynomolgous CD8, and/or a rhesus CD8). Diabodies are taught (paragraph 0060, 0071).
Chen does not specifically exemplify treating a human patient comprising administering to patient diagnosed with cancer a binding construct that binds to human CD8, wherein the first dose comprises: a labeled antigen-binding construct providing a radiation activity of about 0.5 to 3.6 mCi; and about 10 mg or less of the antigen-binding construct.
However, it would have been obvious to one of ordinary skill in the art at the time of the invention to optimize the dosage of radiolabeled anti-CD8 construct for monitoring the efficacy of anti-tumor therapy over time in a human subject by monitoring T-cell presence in a tumor over time before and after administering a radiolabeled anti-CD8 antibody conjugate after administration of the anti-tumor therapy and comparing images, including indication of tumor response to the anti-tumor therapy and performing monitoring over time over the course of therapy. One of ordinary skill in the art would have been motivated to select an amount of anti-CD8 antibody within the claimed range, with a reasonable expectation of success, because 10 mg 89Zr-huOKT8.v11-OA-LALAPG containing a 1 mCi radiation dose was administered to a monkey (paragraph 0265), and 1, 5 or 20 mg are the proposed amounts for use in human patients (Table 13). Furthermore the claims differ from the reference by reciting a dosage amount of the active component. However, the administration of various pharmaceutical compositions provided at varying amount of active agent is within the level of skill of one having ordinary skill in the art at the time of the invention. It has also been held that the mere selection of proportions and ranges is not patentable absent a showing of criticality. See In re Russell, 439 F.2d 1228 169 USPQ 426 (CCPA 1971).
Conclusion
No claims are allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEAH H SCHLIENTZ whose telephone number is (571)272-9928. The examiner can normally be reached Monday-Friday, 8:30am - 12:30pm EST.
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/LHS/
/Michael G. Hartley/ Supervisory Patent Examiner, Art Unit 1618