Development of Radioimmunotherapeutic and

Transcription

1 Development of Radioimmunotherapeutic and Diagnostic Antibodies C. Andrew Boswell, Ph.D. Former Post-doctoral Research Fellow Laboratory of Martin Brechbiel, Ph.D. Radioimmune Inorganic Chemistry Section, NCI SNM 2009 Mid-Winter Symposium After Bench to Bedside: Impact on Clinical i l Outcome, Feb. 8, 2009 Disclaimer: C. A. Boswell is currently an employee at Genentech, Inc. The contents of this presentation, however, are based entirely on research and writings created prior to his employment and do not necessarily reflect the views of Genentech, Inc.

2 Primary Reference for Today s Presentation Nuclear Medicine and Biology 34 (2007)

3 Current FDA Approved Radioimmunodiagnostic & Radioimmunotherapeutic (RIT) Antibodies Satumomab OncoScint * 111 In-murine anti- colorectal, ovarian 1992 pendetide TAG-72 IgG Nofetumomab merpentan Verluma * 99m Tc-murine anti- EGP-1 Fab' Arcitumomab CEA-Scan * 99m Tc-murine anti- CEA Fab' Capromab ProstaScint 111 In-murine anti- pendetide PSMA Ibritumomab tiuxetan Zevalin 90 Y-murine anti-cd20 IgG + another Ab small cell lung 1996 colorectal 1996 prostate 1996 B-cell lymphoma 2002 Tositumomab Bexxar 131 I-murine anti-cd20 B-cell lymphoma 2003 Anti-B1 IgG + unlabeled tositumomab Boswell and Brechbiel, Nucl Med Biol 34 (2007)

4 Current Marketing Status of FDA-Approved Diagnostic Antibodies for Oncologic Imaging OncoScint is no longer commercially available Verluma is no longer marketed in the US CEA-Scan is not marketed in the US ProstaScint is the only approved oncologic radioimmunodiagnostic agent that is still actively marketed and available comparison of sensitivity to FDG-PET Boswell and Brechbiel, Nucl Med Biol 34 (2007)

5 FDA-Approved RIT Antibody: Zevalin Zevalin ( 90 Y-Ibritumomab Tiuxetan) is an FDA-approved therapeutic radiopharmaceutical indicated for the treatment of patients with relapsed or refractory low-grade or follicular B-cell non-hodgkin's lymphoma SCN DOSAGE AND ADMINISTRATION Day 1: Administer rituximab 250 mg/m 2 IV. Within 4 hours after unlabeled Ab infusion, administer 5 mci In-111 Zevalin IV Day 7, 8, or 9: Administer rituximab 250 mg/m 2 IV infusion. If platelets 150,000/mm 3 : Within 4 hours after unlabeled Ab infusion, administer 0.4 mci/kg Y-90 Zevalin IV If platelets 100,000 but 149,000/mm 3 : Within 4 hours after unlabeled Ab infusion, administer 0.3 mci/kg Y-90 Zevalin IV N N CO 2 HCO 2 H CO 2 H N CO 2 H CO 2 H Effective 12/22/07, CTI (Cell Therapeutics, Inc. Seattle, WA) has assumed the sales, marketing, and development rights in the U.S. for Zevalin from Biogen Idec 1B4M-DTPA (MX-DTPA) tiuxetan

6 FDA-Approved RIT Antibody: Bexxar The BEXXAR (GlaxoSmithKline) therapeutic regimen (Tositumomab and 131 I-Tositumomab) is indicated for the treatment of patients with CD20 antigen-expressing expressing relapsed or refractory, low-grade, follicular, or transformed non-hodgkin s lymphoma DOSAGE AND ADMINISTRATION Dosimetric Step: IV Infusion of 450 mg Tositumomab over 60 minutes followed by IV infusion of 5.0 mci 131 I Tositumomab (35 mg) over 20 minutes If whole-body dosimetry/biodistribution is acceptable, then Therapeutic Step: IV Infusion of 450 mg Tositumomab over 60 minutes followed by prescribed therapeutic dose of Iodine 131 I Tositumomab (35 mg) over 20 minutes (enough to deliver 75 cgy TBD or 65 cgy TBD if platelets are between 100, ,000/mm 3 )

7 A Checklist for Success in Radiolabeled Antibody Development Isotope Choices Isotope Delivery Antibody/Vector Antigen/Receptor Other Considerations

8 Radioimmunotherapeutic Antibodies Diagnostic Antibodies Criteria for Each? Mutually compatible, or Apples and Oranges? Successive or Concurrent?

9 Pre-Therapy Dosimetry Radioimmunotherapeutic Antibodies Individualized Screening for Receptor Expression Post-Therapy Monitoring Diagnostic Antibodies Criteria for Each? Mutually compatible, or Apples and Oranges? Successive or Concurrent?

10 Diagnostic & RIT Antibodies: What Criteria i Govern Success? ISOTOPE: DECAY MODE, & ENERGY α / β - / β + / Auger e - for therapy γ / β + for imaging ANTIBODY ENGINEERING Murine vs. Chimeric Human; IgG vs. Fab; etc. CARRIER FOR ISOTOPE DELIVERY Halogen vs. Metal- Chelate Conjugate Stability, Residualization, etc. TARGET ANTIGEN Over-expressed, specific targets Not expressed on normal tissue

11 Requirements for Ab-Based Imaging versus RIT Imaging Mutual Therapy -match particle range with tumor size - match biological - avoid toxicity due to and physical t 1/2 s hematopoietic, ti renal, with uptake / and hepatic doses clearance - ensure proper - choose isotope with - stable chelation / (sub)cellular l localization li desirable emissions attachment for α and especially for imaging Auger emitters - choose target that - achieve sufficient is accessible and penetration within sufficiently overexpressed necrotic tumor cores - enhance tumor cell killing using combined modalities

12 Periodic Table of the Elements Milenic, Brady, and Brechbiel Nature Rev Drug Disc 2004

13 Physical Half-lives of Selected PET Radionuclides: Considerations for Success in Diagnostic Imaging g Isotope Half-life Max β+ β+ energy (MeV) abund. 66 Ga 945h % 64 Cu 12.8 h % 86 Y h % 94m Tc 53 min % 89 Zr 78.4 h % Note that the biological half-life of antibodies is on the order of several days, not hours or minutes! Difficulties in chelation chemistry must also be considered Complications also arise due to interfering gamma emissions, especially those whose gamma energies are near 511 kev Mini-Derenzo Phantom Images Molecular Imaging in Oncology By Martin G. Pomper, Juri G. Gelovani

14 Mean Particle Ranges (mm) of Auger, α, and Various β - -Emitters 169 Er 67 Cu 177 Lu 175 Yb 166 Dy α emitter Auger e - 64 Cu 131 I 153 Sm 109 Pd 111 Ag 186 Re 198 Au residual or disseminated 165 Dy intermediate 188 Re 90 Y 166 Ho gross solid tumors Matching tumor size with beta particle mean range is a logical therapeutic strategy! adapted from Boswell and Brechbiel, Nucl Med Biol 34 (2007)

15 α- vsβ-particle Radioimmunotherapy α-particle µm range 5-8 MeV β-particle 1-10 mm range MeV Milenic, DE, Brady, ED, and Brechbiel, MW Nature Rev. Drug Disc. 2004, 3, 488.

16 Importance of Proper Therapeutic Radionuclide Selection German Phase II trial I-anti-CEA Ab (labetuzumab) 19 colorectal cancer (CC) patients after salvage resection of liver mets The majority of patients received only a single infusion of mci/m 2 -- survival rate was 51% at 5 years, compared with the expected rate of 28% derived from an analysis of 1,596 patients U.S. clinical trial Y-labetuzumab was terminated One might speculate that the dubious choice of 90 Y for treating post-operative residual disease in CC patients may have contributed: tib t The purpose of this trial is to determine the safety of 90 Y- hmn14 at different dose levels in the treatment of residual colorectal cancer following recent surgery. source:

17 Choice of Carrier for Isotope Poor choice of halogenation / conjugation chemistry can limit success of imaging/rit, although it causes considerably fewer disasters relative to poor choice of target Several potentially useful isotopes for imaging and/or therapy are often avoided to spare extra work involved (e.g., 177 Lu, 89 Zr, 64 Cu, 67 Cu, 212 Bi, 213 Bi, 225 Ac, 212 Pb, 111 Ag, 198 Au) Due to the extra considerations involved in stable chelation, a limited pool of radioisotopes (e.g., 131 I, 90 Y) are often selected merely based on tradition, familiarity, or convenience New chemical methodologies for incorporating such alternative or exotic isotopes, many of which are readily available commercially and have shown great promise in preclinical studies, should be implemented into future clinical studies

18 Minimal Criteria For Successful mab Conjugation (1) The chelate must form a metal complex which has sufficient thermodynamic and kinetic stability to prevent loss of radionuclide in vivo; (2) Conjugation must not alter mab specificity; (3) Conjugation must not alter the rate of mab catabolism; Milenic, DE, Brady, ED, and Brechbiel, MW Nature Rev. Drug Disc. 2004, 3, 488.

19 Nature of Antibody Although murine Abs may succeed in immunosuppressed lymphoma patients, adequate treatment of carcinomas requires chimeric or humanized, non-immunogenic Abs to avoid HAMA/ATA Slow accumulation / clearance of IgG molecules warrants the exploration and development of smaller Ab fragments and intermediate minibodies Pretargeting approaches, including those exploiting the avidin-biotin chemical complex, may aid in reduction of normal organ toxicity during RIT and increase tumor:background ratios in imaging g

20 Nature of Antibody Phase I study of 90 Y-CC49, a murine Ab that binds to TAG- 72, in advanced non-sclc (2005) There were no objective tumor responses; immunogenicity and hematologic toxicities were problematic Disappointing results warranted development of a Humanized version of CC49 Because of the immunogenicity of the murine compound, future studies are planned using a humanized version of CC49. Source: Cancer Biother Radiopharm Oct;20(5):

21 Target Tumor Receptor / Antigen Perhaps the most prevalent underlying cause of pre-clinical and clinical failures in both imaging and RIT is a poor choice of target receptor Antigens located on the extracellular membrane surface often represent attractive targets. Internalization of the receptor may carry radionuclides intracellularly to inflict greater damage to nuclear DNA Also may deplete the availability of that same antigen

22 Normal Organ Expression of Target Systemic injection of a streptavidin-anti-ep-cam antibody conjugate (SA-NR-Lu-10); radiolabeled biotin with a chase step: either HSA-galactose-biotin or biotin-lc-nm-(gal-nac) NAc) Impressive pre-clinical results with this 3-step pretargeting strategy Phase II clinical trial of 90 Y-DOTA-biotin pre-targeted by NR-LU-10 antibody/streptavidin in metastatic colon cancer patients The overall response rate was only 8%, and both hematological l (8% grade 3 neutropenia, 8% grade 3 thrombocytopenia) and non-hematological (16% grade 3 diarrhea) toxicities were observed. Results were plagued by healthy bowel expression of Ep-CAM receptor A poor choice of target receptor, rather than the pretargeting strategy, was the major pitfall. Clin Cancer Res 2000; 6 :406-14

23 Target Accessibility 111 In-capromab pendetide scan - cytoplasmic epitope in bone metastases is Ab-inaccessible Target is an intracellular epitope (N-terminus) of the PSMA molecule that is inaccessible to circulating Ab Severely compromised by its inability to image bone metastases Unfortunately, bone is the first site of metastatic prostate cancer in 72% of patients. More advanced Abs such as J591 target the extracellular domain of PSMA and therefore may provide significant benefits in the imaging i of prostate t cancer. Nature Clinical Practice Urology (2006) 3,

24 Shed/Secreted Targets Shed/secreted antigens include NHL idiotype, CEA, and TAG-72 Such targets might be considered less optimal Shedding or secretion from the cell surface, circulation in the blood, residence in the interstitial compartment Freely circulating antigen binds administered Ab, thereby diverting it from reaching the cancer cells Antibodies that target these antigens will bind circulating target antigen, compromising the amount of Ab for binding to tumor

25 Reasons for Clinical Trial Failures Poor predictability of preclinical models Low enrichment levels of molecular target within tumors Inappropriate p clinical decision-making in Phase I/II Phase III transition Inappropriate clinical study design Saijo, N., Cancer Sci 2004, 95, (10),

26 RIT & Decision Making Isotopes How do we pick them and why? Antibodies Cost Availability Convenience How do we pick them and why? Good target Availability Convenience Disease location and presentation and scale How do we rationally combine antibodies, targets and isotope? (Do we?)

27 A Checklist for Success in Radiolabeled Antibody Development Isotope Choices Isotope Delivery Antibody/Vector Antigen/Receptor Other Considerations

28 Considerations for Stand-Alone Immuno-PET/SPECT Agents Kidney/renal cancer accounts for about 3% of all cancers - ~12,000 kidney cancer deaths each year With early diagnosis, the survival rate % 35,000 new cases of renal cancer per year in the US and 700,000 worldwide However, there is currently no FDA-approved stand-alone alone radioimmunodiagnostic imaging agent for renal cancer For comparison, > 29 million Americans have been prescribed Lipitor (atorvastatin), and annual worldwide sales are over $12 billion in 2007 FDG-PET may have more favorable properties as a widely used stand-alone imaging i agent as it is useful in a wider range of cancer types

29 Cost of Standard Therapy vs. Radioimmunotherapy Generally speaking, radionuclide cost significantly elevates the overall cost of RIT agents per dose (about $25,000 per treatment) relative to non-radioactive therapies However, fewer administered doses of RIT are typically necessary (one dose is usually enough) Please see the references below for various viewpoints and opinions regarding this issue: Gordon et al., Clin Lymphoma 2004, 5, (2), Ghielmini et al., Blood 2004, 15, David RB, Pharmacy & Therapeutics J 2006, 31, (3),

30 Medicare Funding Congress Overrides Bush Veto on Medicare Bill, Cell Therapeutics Zevalin Reimbursement Survives Bill would allow doctors who prescribe Zevalin over an 18-month period to continue getting paid $21,000 per patient for the treatment, instead of the $15,000 that had been proposed by Medicare Congress voted to overrule Bush s veto, which would have killed a provision that extended the current reimbursement rate for doctors who prescribe Zevalin The Medicare Improvements for Patients and Providers Act of 2008, as passed by the U.S. House of Representatives on 6/24/08 and the U.S. Senate on 7/9/08, will continue the 2007 reimbursement methodology for therapeutic radioimmunotherapies until 1/1/10, giving drug manufacturers and CMS time to determine future reimbursement methods and levels Article Published on Web by Luke Timmerman, National Biotechnology Editor for Xconomy (Seattle, WA), 7/16/08 ltimmerman@xconomy.com

31 FDA Approval vs. Clinical Use New York Times, 2007 by Alex Berenson: Market Forces Cited in Lymphoma Drugs Disuse Fact: NHL is the 5th most common cancer in the US, with 60,000 new cases and almost 20,000 deaths a year Yet fewer than 2,000 patients received Bexxar or Zevalin in 2006, only about 10% of the suitable candidates for the drugs Nuclear medicine specialists, but not oncologists, are licensed to administer i Bexxar and dzevalin

32 RIT & Decision Making Combination therapies (e.g. chemo + RIT) may also hold promise as opposed to RIT as a stand alone therapy However, several criteria must be carefully considered: Likelihood that different patients will respond to different combination therapies due to individual differences in receptor expression a situation that may be probed by imaging! Added cost of multiple drug combinations (i.e., cocktails ) can push them financially out of reach by challenging the healthcare system and third-party payers Balancing the benefits of personalized medicine i against practical and financial realities

33 Ongoing Phase II/III Trials: Are Wiser Choices Finally Being Made? Sponsor Agent/Target Cancer Indication Phase GlaxoSmithKline 131 I-tositumomab vs. ibritumomab tiuxetan non-hodgkin's III lymphoma Immunomedics, Inc. 99m Tc-LL2 (LymphoScan) non-hodgkin's lymphoma III Immunomedics, Inc. 90 Y-epratuzumab (hll2) non-hodgkin's II lymphoma Ludwig Institute for Cancer Research 111 In-cG250 (phase I) and 177 Lu-cG250 (phase II), (a chimeric mab) advanced renal cell carcinoma II Memorial Sloan-Kettering 213 Bi-M195 (humanized anti-cd33 mab) advanced myeloid II Cancer Center / NCI cancer Fred Hutchinson Cancer Research Center 131 I-BC8 acute myeloid leukemia or myelodysplastic syndromes II Duke University / NCI 211 At-81C6 (antitenascin human/mouse chimeric mab) primary or metastatic brain tumors II Weill Medical College of Cornell University / Columbia University it 177 Lu -J591 prostate cancer II NCI 99m Tc-arcitumomab (IMMU-4), comparison study with FDG colorectal carcinoma II

34 Ongoing Phase I Trials: Are Wiser Choices Finally Being Made? Sponsor Agent/Target Cancer Indication Phase Radboud University / Immunomedics, Inc. hmn-14xm In-IMP-205 (pretargeted) colorectal carcinoma Immunomedics, Inc. 90 Y-HuPAM4 pancreatic cancer I Ludwig Institute for Cancer Research Ludwig Institute for Cancer R h / W th 131 I-huA33 (in combination with capecitabine) 111 In-CMD-193 (a humanized mab li k d t th t i li h i i ) metastatic colorectal carcinoma advanced tumors i th L i Y antigen Research / Wyeth linked to the toxin, calicheamicin) expressing the Lewis-Y Sidney Kimmel Comprehensive Cancer Center / NCI Memorial Sloan-Kettering Cancer Center / NCI 111 In-labeled humanized PAM4 IgG pancreatic cancer I 131 I-8H9 CNS or leptomeningeal cancer NCI 131 I-TNT-1/B glioblastoma multiforme I I I I I

35 Acknowledgements Martin W. Brechbiel, NCI Bill Eckelman, UCSD Kimberly Hanson-Kay, SNM