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LESLIE AND YOUNES

Antibody-Drug Conjugates in Hematologic Malignancies


Lori A. Leslie, MD, and Anas Younes, MD
OVERVIEW
Antibody-drug conjugates (ADCs) are agents composed of a monoclonal antibody linked to cytotoxic molecules. By specically delivering cytotoxic agents to cells expressing surface antigens of interest, ADC technology allows for the targeted use of highly toxic agents resulting in increased efcacy against malignant cells and decreased damage to normal tissue. Effector agents can be small molecules, radioisotopes, proteins, or bacterially derived toxins. Over the past several decades, ADCs have been evaluated in a variety of preclinical models of hematologic malignancies, as well as early-phase clinical trials with limited success. More recently, advancements in linkage technology, improvements in cytotoxin selection, and use of smaller conjugates containing partial rather than complete antibodies have drastically improved the potential clinical value of ADCs. In the future, ADC technology may be used to restore tumor suppressor activity, target the microenvironment, or replace nonfunctional enzymes. In this review we will discuss select ADCs in various stages of development for use in hematologic malignancies including lymphoma, multiple myeloma, and leukemia.

n the era of targeted therapy the goal is to develop highly effective, specifc agents with wide therapeutic indices. Most cancer therapies currently in use either target oncogenic drivers specifcally with the risk of inducing tumor resistance mechanisms or nonspecifcally target rapidly dividing cells with the risk of toxicity to normal tissue. The U.S. Food and Drug Administration (FDA) approval of the anti-CD20 monoclonal antibody rituximab in 1997 sparked an increased interest in using antibodies to target malignant cells. Recent advancements in conjugate technology have allowed for the translation of antibody-drug conjugates (ADCs) into clinical use. ADCs are bioconjugates composed of a monoclonal antibody, linker region, and effector molecule. Generally, the antibody binds the target antigen or receptor on the surface of a cell. The complex is endocytosed and transported to lysosomes where the effector molecule is released into the cytoplasm leading to cell toxicity. Because the large molecular size of early ADCs limited delivery, modern ADCs use smaller modifed antibodies or portions of antibodies. Trials of early ADCs using classic chemotherapeutics as effector molecules resulted in disappointing response rates because of low cytotoxicity at the deliverable dose. Through bioconjugation, highly toxic agents can now be selectively delivered to target cells with a wide therapeutic index. Effector molecules currently in use include proteins and small molecules such as the minor DNA-binding agent calicheamicin; tubulin depolymerization agents maytansinoids (DM1

or DM4) and auristatins (MMAE or MMAF); and bacterial derived agents such as diphtheria or Pseudomonas exotoxins. Linker selection is a crucial determinant of ADC effcacy. Cleavable linkers such as hydrazones and disulfdes are activated in the acidic lysosomal environment or the reductive cytosolic environment, respectively, but unintentional systemic toxin release is relatively common because of the nonspecifc nature of these reactions. Dipeptide noncleavable linkers are more stable in circulation because they are activated by specifc lysosomal proteases, reducing the potential for systemic release. Rather than releasing effector molecules at the site of intended activity, thioethers are noncleavable linkers in which intracellular degradation of the attached antibody leads to effector activation. The number of effector molecules linked to a single antibody determines properties such as tendency to aggregate systemically, effcacy of endocytosis, half-life, and ability to bind target antigens. For the majority of ADCs, the ideal antibody drug ratio to maximize effcacy and delivery is 1:4. There are several additional factors to consider when designing an ADC. Malignant cells typically do not express novel markers to avoid clearance by the hosts immune system, but they may express aberrantly high concentrations of normal surface markers ideal for targeting. Rapid internalization of the antigen-antibody complex on binding is another important target quality, as receptor-mediated endocytosis is necessary for the activity of most effectors. Conjugate stability in circulation, timing of effector release,

From the Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; Lymphoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY. Authors disclosures of potential conicts of interest are found at the end of this article. Corresponding author: Anas Younes, MD, Lymphoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 330, New York, NY, 10065, email: younesa@mskcc.org. 2013 by American Society of Clinical Oncology.

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and minimization of neutralizing antibody production must also be optimized. With these considerations in mind, various ADCs have been designed for use in patients with hematologic malignancies, including lymphoma, multiple myeloma, and leukemia.

CD22
CD22 is involved in inhibitory BCR signaling and prevention of autoimmunity. Similar to CD19, it is rapidly internalized on antigen binding. The modest ORRs of 10% to 18% achieved with the naked anti-CD22 monoclonal antibody, epratuzumab, in B-cell NHL have drastically increased with CD22-directed ADCs.4,5 Inotuzumab ozogamicin (CMC-544), an anti-CD22calicheamicin ADC, has shown promising single-agent activity in patients with RR indolent B-cell NHL. In a phase II study of 43 patients with RR indolent or follicular lymphoma (FL) receiving 1.8 mg/m2 of inotuzumab ozogamicin every 28 days, the ORR was 53% (CRR 19%) with a 6-month progression-free survival (PFS) rate of 59%. Of the 35 patients with FL, the ORR was 66% and 6-month PFS rate was 67%. Common AEs were cytopenias, nausea, fatigue, and increased liver enzymes.6 In a phase I/II trial of inotuzumab ozogamicin and rituximab in patients with RR B-cell NHL, the combination was well-tolerated with manageable AEs similar to those of inotuzumab ozogamicin and rituximab monotherapies, with MTDs of 1.8 mg/m2 and 375 mg/m2, respectively. In FL (39 patients), diffuse large B-cell lymphoma (DLBCL, 42 patients), and aggressive NHL (30 patients) the ORRs were 87%, 74%, and 20%, respectively.7 Preliminary results of a phase I/II trial of DCDT2980S, an anti-CD22 antibody linked to MMAE, revealed early evidence of clinical activity in 35 patients with RR indolent and aggressive B-cell NHL. The MTD was 2.4 mg/kg and the most common AEs were diarrhea, fatigue, nausea, neutropenia, and peripheral edema. Of the 3 patients with DLBCL treated at the MTD, 2 patients (67%) had greater than 75% decrease in tumor burden with complete metabolic response on PET. Two additional patients with DLBCL achieved a partial response (PR) and underwent autologous stem-cell transplantation (ASCT). One patient (9%) with FL achieved PR at a dose level of 1.8 mg/kg. Enrollment in two expansion cohorts at the MTD is ongoing.8

LYMPHOMA
CD19
CD19 is part of the B-cell receptor (BCR) complex. Similar to CD20, CD19 is expressed on the surface of B-lymphocytes throughout development with loss of expression on plasma cells. Unlike CD20, CD19 is rapidly internalized on antigen binding. In a phase I/II study of the CD19 monoclonal antibody, MEDI-551, in patients with relapsed or refractory (RR) B-cell NHL, the objective response rate (ORR) was 26%.1 Given the activity of naked anti-CD19 monoclonal antibodies and its internalization on antibody binding, CD19 is a rational target for cytotoxic ADCs. A phase I study of the anti-CD19-DM4 conjugate, SAR3419, in RR B-cell non-Hodgkin lymphoma (NHL) revealed a maximum tolerated dose of 55 mg/m2 weekly. Doselimiting toxicities were reversible corneal changes and peripheral neuropathy. Other adverse events (AE) were grades 1 to 2 hepatotoxicity and myelosuppression. Of the 22 patients who received drug at the maximum tolerated dose, the ORR was 36% (complete remission rate (CRR) 14%) with a response duration of 6 to at least 12 months.2 Another phase I trial of SAR3419 in 39 patients with RR B-cell NHL established a maximum tolerated dose (MTD) of 160 mg/m2 every 21 days with similar dose-limiting toxicities. Of the 17 evaluable patients who received drug at the MTD, the ORR was 24%. Of those with rituximab-refractory disease, 47% experienced reduction in tumor size. The duration of response at all dose levels was 13.9 to at least 33.1 weeks.3

CD30 KEY POINTS


Antibody-drug conjugates (ADCs) use the specicity of monoclonal antibodies to deliver potent cytotoxic agents with a wide therapeutic index. Effector agents linked to antibodies are typically potent anticancer drugs that are too toxic for systemic use. Selecting a cell surface target that is rapidly internalized on antibody binding allows for intracellular delivery of cytotoxins. The anti-CD30 ADC brentuximab vedotin is an example of an ADC that has been recently approved by the United States Food and Drug Administration (FDA), has changed the treatment paradigm of relapsed or refractory Hodgkin lymphoma, and has promise for use in the upfront setting. In the future, ADCs may be used to restore tumor suppressor function or to replace nonfunctional enzymes in a variety of disease processes.

CD30 is a member of the tumor-necrosis factor receptor family, expressed on activated T and B-lymphocytes, and rapidly internalized on antigen binding. Expression is increased in anaplastic large cell lymphoma (ALCL), classic Hodgkin lymphoma (HL), select cases of NHL, and embryonal germ cell tumors. Although studies of naked anti-CD30 monoclonal antibodies in CD30 lymphomas were disappointing with ORRs of less than 10%,9 the development of CD30directed ADCs is changing the treatment paradigm for CD30 lymphomas. Brentuximab vedotin (SGN-35), an anti-CD30-MMAE ADC, was granted accelerated approval by the FDA in 2011 for patients with RR HL with ASCT failure or ineligibility and patients with ALCL after failure of at least one combined chemotherapy regimen. The approved dosage of brentuximab vedotin is 1.8 mg/kg given every 21 days for a maximum of 16 cycles.10 The most common AEs are peripheral neuropathy, cytopenias, and fatigue. Approval for HL was on the basis of
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TABLE 1. Antibody-Drug Conjugates in Hematologic Malignancies


Target CD3 CD19 CD19 CD22 CD22 Antibody-Drug Conjugate A-dmDR390-bisFv(UCHT1) MEDI-551 SAR3419 Epratuzumab Inotuzumab ozogamicin, CMC544 Cytotoxic Conjugate Diphtheria toxin A Maytansinoid, DM4 Calicheamicin Phase I I/II I/II I I/II I/II II II I CD22 Inotuzumab ozogamicin with rituximab Calicheamicin I/II Disease T-cell NHL B-NHL NHL NHL Indolent/FL Aggressive ALL Indolent/FL DLBCL Indolent, FL DLBCL Aggressive CD22 CD22 CD22 CD19 and CD22 CD30 DCDT2980S CAT-3888, BL22 Moxetumomab pasudotox , CAT-8015, HA22 RFB4 & HD37-dgRTA, Combotox MDX30 MMAE PE38 PE38 Deglycosylated Ricin A I II I I I/II DLBCL Indolent HCL (1 cycle) HCL (2 cycles) HCL B-cell ALL HL, ALCL, or CD30 TNHL HL ALCL CD30 NHL CD30 Brentuximab vedotin, AVD CHP MMAE I I CD33 CD33 CD33 CD33 CD56 CD74 CD74 CD138 M195 Gemtuzumab ozogamicin, Mylortag AVE9633 Hum-195/rGel Lorvotuzumab mertansine, IMGN901 Milatuzumab Milatuzumab-doxorubicin, hLL1-DOX BT062 Calicheamicin Maytansinoid, DM4 Gelonin Maytansinoid, DM1 Doxorubicin Maytansinoid, DM4 I II I I I I I/II I/IIa AML AML, Age60 AML AML, MDS, CMML MM MM MM CLL, NHL MM 0 4 (48) HL ALCL 32 57 14 92 88 0 30 26 2 0 0 0 CRR% 20 12 14 6 6 18 19 25 47 46 0 PRR% (SD or MR) 40 14 22 12 4 39 34 25 25 40 6 8 (35) ORR% 60 26 36 24 18 10 57 53 15 87 74 20 22 9 50 82 86 6 8 27 30 9 25 8 Ref 16 1 2 3 4 5 28 6 29 7

CD30

Brentuximab vedotin, SGN-35, ADCETRIS

MMAE

II

40 29 19 4 12 0(15) 2 0 (27) 7 (11) 0 (19)

73 86 33 96 100 0 30 26 4 0 18 0 Ongoing 52

11 12 13 14 15 20 21 23 24 18 19 17

Abbreviations: ALCL, anaplastic large cell lymphoma; ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; CLL, chronic lymphocytic leukemia; CMML, chronic myelomonocytic leukemia; CRR, complete response rate; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; HCL, hairy cell leukemia; HL, Hodgkin lymphoma; MDS, myelodysplastic syndrome; MM, multiple myeloma; MMAE, monomethyl auristatin E; MR, minimal response; NHL, non-Hodgkin lymphoma; ORR, overall response rate; PE38, pseudomonas exotoxin; PRR, partial response rate; SD, stable disease.

results from a multicenter phase II trial in which 102 patient with relapsed HL after ASCT achieved an ORR of 73%, CRR of 32%, and partial response rate (PRR) of 40% with median durations of response 6.7, 20.5, and 3.5 months, respectively.11 Approval for ALCL was on the basis of a multicenter phase II trial of 58 patients with CD30-positive ALCL with at least one prior multiagent chemotherapy regimen that
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revealed an ORR of 86%, CRR of 57%, and PRR of 29%, with median durations of response 12.6, 13.2, and 2.1 months, respectively.12 Brentuximab vedotin has also shown activity in other NHL subtypes. Interim results of a multicenter phase II trial of brentuximab vedotin in 53 patients with RR CD30-postive NHL revealed an ORR of 33% (CRR 14%, PRR 19%) in 36

PRESENT AND FUTURE OF ADCS IN HEMATOLOGIC MALIGNANCIES

FIG 1. Target expression in hematologic malignancies.


Abbreviations: HL, Hodgkin lymphoma, B-NHL, B-cell non-Hodgkin lymphoma, T-NHL, T-cell non-Hodgkin lymphoma, MM, multiple myeloma, CLL, chronic lymphocytic leukemia.

evaluable patients. Encouraging subtypes included nonprimary mediastinal DLBCL (15 patients, ORR 47%, complete remission rate (CRR) 20%, PRR 27%); angioimmunoblastic T-cell lymphoma (5 patients, ORR 60%, CRR 40%, PRR 20%); and gray zone lymphoma (5 patients, PRR 40%). Notably, the degree of CD30 expression did not correlate with likelihood of response.13 Brentuximab vedotin is currently being evaluated in combination with chemotherapy in the upfront setting. In a phase I study, 51 patients with untreated HL were given 0.6 mg/kg to 1.2 mg/kg of brentuximab vedotin with doxorubicin, bleomycin, vinblastine, and dacarbazine (BVABVD) or 1.2 mg/kg of brentuximab vedotin with AVD (BVAVD) on day 1 and 15 of a 28-day cycle for up to 6 cycles. DTLs were not observed at the maximum planned dose. Common AEs were similar to those with ABVD or brentuximab vedotin monotherapies. Of note, 11 of 25 (44%) patients treated with BVABVD experienced pulmonary toxicity resulting in 2 deaths, compared with 0% in the BVAVD group. PET-CT after 2 cycles was obtained in 48 patients with complete metabolic response observed in 100% (BVABVD) and 92% (BVAVD) of patients. At the end of treatment, the ORR was 96% (CRR 95% for BV-ABVD, CRR 92% for BVAVD).14 A phase I study of 1.8 mg/kg of brentuximab vedotin given in combination with cyclophosphamide, doxorubicin, and prednisone (BV-CHP) for up to 6 cycles followed by maintenance single-agent brentuximab vedotin in 26 patients with untreated ALCL (19 patients) or other mature NK/T cell lymphomas (7 patients) revealed an ORR of 100% (CRR 88%, PRR 12%). Grade 3 or higher AEs included febrile neutropenia, nausea, and pulmonary embolism.15 Randomized trials of BV-containing regimens compared with standard ABVD in HL or CHOP in T-cell lymphomas are underway. Further studies of brentuximab vedotin in combination with bleomycin-containing regimens should be avoided because of increased risk of life-threatening pulmonary toxicity.

patients with RR T-cell NHL. The MTD was not reached. AEs were dose-dependent and included transient fever, lymphopenia, CMV or EBV viremia, and liver function test abnormalities. Of the 10 evaluable patients, the CRR was 20% and PRR was 40%.16 A phase I/II trial in patients with CD3positive refractory T-cell leukemia or lymphoma is currently in recruitment (NCT00611208).

MULTIPLE MYELOMA
CD138
Among lymphoid cells, CD138 is a sensitive and specifc marker of plasmacytoid differentiation that is internalized on ligand binding. In a phase I/II study of BT062, an antiCD138-DM4 ADC, in 32 patients with RR multiple myeloma, the MTD was 160 mg/m2 and the dose-limiting toxicity was mucositis. Common AEs were epithelial in nature, including stomatitis, hand-foot syndrome, xerophthalmia, and blurred vision. Of the 27 evaluable patients, clinical response rate was 52%, with 4% demonstrating PR and 48% demonstrating minimal response (MR) or stable disease (SD).17 The MTD cohort has been expanded, results are currently unavailable.

CD56
CD56, or neural cell adhesion molecule, is involved with cellcell adhesion. It is expressed on a variety of normal and malignant hematolymphoid cells, including NK cells, activated T cells, myeloid leukemia, NK/T-cell lymphomas, and multiple myeloma. Results from the expansion cohort of a phase I study of the anti-CD56-DM1 ADC, lorvotuzumab mertansine (IMG901), in 28 evaluable patients with RR CD56positive multiple myeloma revealed an ORR of 18% (PRR 7%, MRR 11%). The MTD was 112 mg/m2 and grade 3 AEs were fatigue, renal failure, and absence of deep tendon reflexes.18 Considering that clinically signifcant myelosuppression was not observed, a phase I study of lorvotuzumab mertansine in combination with lenalidomide and dexamethasone in patients with RR multiple myeloma is ongoing (NCT00991562).

CD3
A component of the T-cell receptor (TCR) complex, CD3 is a specifc surface marker expressed throughout T-cell development and internalized on ligand binding. In a phase I trial, the bivalent anti-CD3 antibody linked to diphtheria toxin, A-dmDT390-bisFv(UCHT1), was administered to 12

CD74
CD74 is the invariant chain of the MHC class II complex expressed on the surface of antigen presenting cells and
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lymphocytes, is internalized on ligand binding, and has a high degree of expression in multiple myeloma. In a multicenter phase I trial of the naked anti-CD74 monoclonal antibody, milatuzumab, in patients with RR multiple myeloma the MTD was not reached, and 19% of patients receiving the highest dose levels maintained stable disease.19 Phase I/II trials of the hLL1-DOX, a milatuzumabdoxorubicin ADC, in patients with RR multiple myeloma (NCT01101594) and CLL or NHL (NCT01585688) are currently in recruitment.

LEUKEMIA
CD33
Although early phase trials of the naked CD33 monoclonal antibody, M195, yielded disappointing results in patients with acute myelogenous leukemia (AML),20 ADCs targeting the myeloid-specifc transmembrane receptor CD33 have shown activity. Gemtuzumab ozogamicin (Mylortag), an anti-CD33-calicheamicin ADC, was granted acceleratedapproval by the FDA in 2000 for the treatment of RR AML in patients over age 60 or those who are not candidates for standard chemotherapy. Approval was on the basis of aggregate data from phase I and phase II studies revealing a CRR with complete hematopoietic recovery of 16% and a CRR with persistent thrombocytopenia of 14%, for an ORR of 30%. The ORR for patients over the age of 60 was 26%. The most common AEs were myelosuppression and hepatotoxicity.21 In 2009, a planned interim analysis of a follow-up phase III trial evaluating gemtuzumab ozogamicin in combination with standard induction chemotherapy revealed no improvement in CRR, relapse free survival, postconsolidation disease free survival, or overall survival. Notably, 5.8% of patients in the gemtuzumab ozogamicin arm experienced fatal AEs compared with 0.8% in the control arm.22 Given safety concerns, it was voluntarily withdrawn from the market in 2010, but its use in clinical trials as part of combination therapy in AML continues with stringent safety monitoring. Early results of other anti-CD33 ADCs have been disappointing. In a phase I study, AVE9633, an anti-CD33-DM4 ADC, was administered to 54 patients with AML resulting in 1CR (2%) and 1 PR (2%).23 A phase I study of the anti-CD33gelonin ADC, HuM195/rGel, in 28 patients with AML, chronic myelomonocytic leukemia, or myelodysplastic syndrome revealed an MTD of 7 mg/m2. Of the 22 evaluable patients, there was no CR but 6 (27%) had a 50% decrease in blasts.24 With both agents, hypersensitivity was common but myelosuppression was not observed.

(CRR 25%). Those that did not achieve CR (27 patients) received a second cycle of CAT-3888, resulting in an ORR of 72% (CRR 47%, PRR 25%). Those with splenomegaly greater than 20 cm or a history of splenectomy were less likely to respond. The only grade 3 toxicity reported was hemolytic uremic syndrome (HUS), occurring in 6% of patients.25 A second generation anti-CD22-PE38 ADC, moxetumomab pasudotox (CAT-8015, HA22), demonstrated increased effcacy over CAT-8333 in animal models of hematologic malignancies.26 In a phase I trial of 28 patients with RR HCL, the MTD was not reached. AEs included reversible grade 1 to 2 HUS, hypoalbuminemia, transaminitis, headache, hypotension, nausea, and fatigue. Responses were seen at all dose levels with an ORR of 86% (CRR 46%). The median disease-free survival had not been reached at 26 months.27 Phase I/II trials of moxetumomab pasudotox in patients with CLL, NHL, and acute lymphoblastic leukemia (ALL) are active, two of which have completed recruitment with results pending. The anti-CD22-calecheamicin ADC, inotuzumab ozogamicin (CMC544), has not only shown promising activity in NHL, but also has shown encouraging activity in patients with ALL. A phase II study of inotuzumab ozogamicin in 49 patients with relapsed or refractory ALL revealed an ORR of 57%, with 19% achieving CR and 39% achieving marrow CR with persistent cytopenias. Common AEs were fever, hypotension, and hepatotoxicity.28

CD19/CD22
Similar to the concept of combination chemotherapy, using combinations of monoclonal antibodies linked to the same effector molecules is an area of interest. An ADC composed of anti-CD19/CD22 antibodies linked to deglycosylated ricin A chain, Combotox, was evaluated in a phase I study of 17 patient with RR B-lineage ALL. Disappointingly, only one patient experienced a PR and was able to undergo an autologous stem cell transplant. However, all patients with circulating blasts experienced reduction in blast counts with therapy. Similarly a phase I trial of DT2219ARL, an immunotoxin composed of CD19 and CD22 scFv ligands linked to diphtheria toxin, is currently recruiting adults with relapsed/refractory B-lineage leukemia or lymphoma (NCT00889408).

FUTURE DIRECTIONS
As more is understood about the interaction between malignant cells and their surroundings, ADCs can be used not only to target cell surface antigens but also the microenvironment. In the future, it is possible that ADCs could be used to deliver functional enzymes intracellularly or to restore tumor suppressor function. With further developments in antigen, effector, and linker technology, the specifcity and effcacy of ADCs will continue to improve, creating valuable agents for both monotherapy and combination therapy in hematologic malignancies. Additionally, further correlative biomarker studies will be crucial to improve patient selection.

CD22
CD22 directed ADCs have also been evaluated in patients with leukemia. In a phase II study, the frst generation anti-CD22Pseudomonas exotoxin ADC, CAT-3888 (BL22), was administered to 36 patients with RR hairy cell leukemia (HCL). After one cycle (three doses) of 40 /kg every 48 hours, ORR was 50%
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Disclosures of Potential Conicts of Interest


Relationships are considered self-held and compensated unless otherwise noted. Relationships marked L indicate leadership positions. Relationships marked I are those held by an immediate family member; those marked B are held by the author and an immediate family member. Relationships marked U are uncompensated.

Employment or Leadership Position: None. Consultant or Advisory Role: Anas Younes, Allos Therapeutics; Celgene; Gilead Sciences; Millennium; Novartis; Sano; Seattle Genetics. Stock Ownership: None. Honoraria: None. Research Funding: Anas Younes, Afmed Therapeutics; Gilead Sciences; Novartis; Seattle Genetics; Syndax. Expert Testimony: None. Other Remuneration: None.

References
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