Eary, C. Badger, F. Applebaum, G. Wiseman, D. Matthews, P. Martin, I. Sgouros, D. Zimmer, S.
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Immunotoxin Therapy of Lymphoma M. Grossbard, L. View on Springer. Alternate Sources. Save to Library. The most common adverse reactions were peripheral sensory neuropathy, neutropenia, fatigue, nausea and thrombocytopenia. In USA, Brentuximab vedotin carries a black box warning for progressive multifocal leukoencephalopathy Younes et al, Clinical trials for ADCs against hematological malignancies have increased significantly in recent years.
There are currently at least 11 ADCs in Phase I-II clinical trials for hematological malignancies for which targets, antibodies, linkers, and cytotoxic pay loads have been disclosed Table 3. There are 5 ADCs that use monomethyl auristatin as the cytotoxic compound and 3 ADC that employ maytansine which causes mitosis arrest. This or next year, a market approval could become a reality for Inotuzumab ozogamicin. Table 3. Clinical development of antibody-drug conjugates for treating hematological malignancy. Market Dynamics for ADCs Since the commercialization of the first therapeutic monoclonal antibody product in , as of November , forty-seven naked monoclonal antibody products were approved in US and Europe for the treatment of variety of diseases.
Brentuximab Vedotin Adcetris by Seattle Genetics was approved by the FDA in as the first new therapeutic option for patients with Hodgkin lymphoma in more than 30 years. Brentuximab Vedotin has now become the standard of care for relapsed Hodgkin lymphoma, with more than 20, patients treated, as noted by Jonathan Drachman, M. Brentuximab Vedotin is an antibody-drug conjugate directed to CD30, a defining marker of classical Hodgkin lymphoma, which combines the targeting ability of a monoclonal antibody, attached by a protease-cleavable linker to the cell-killing microtubule disrupting agent, monomethyl auristatin E MMAE.
The drug employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CDexpressing tumor cells. There are more than 50 ADCs at various stages of clinical development, covering a broad spectrum of oncology targets Beck et al, ; Mullard, Glyco- engineering should help with better selection of monoclonal antibodies through optimal pharmacokinetic, potency and toxicity profiles Shah, Glyco-engineering will undoubtedly play major part in further development of better target specific monoclonal antibodies and thus on the ADC market as a whole.
Insufficient understanding of ADCs mechanism of action, inadequate knowledge of the management and understanding of ADCs off-target toxicities, and difficulties in the selection of suitable clinical settings such as patient selection, dosing regimen are some possible explanations for the slow clinical translation of new ADCs. Their clinical outcomes can be further improved by optimizing target selections, binding moieties monoclonal antibody and protein scaffolds , cytotoxic drugs, linkers, conjugation sites, and conjugation chemistries. As many novel ADC technologies mature over time, we expect to see a generation of safer and more effective ADCs for clinical translation and commercialization in the future.
With further developments in antigen, effector, and linker technology, the specificity and efficacy 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 for ADCs against hematological and other malignancies.
Antibody—drug conjugates are one of the fastest growing classes of oncology therapeutics. After half a century of research, the approvals of brentuximab vedotin and trastuzumab emtansine have paved the way for ongoing clinical trials that are evaluating more than 50 further ADC candidates.
Immunoconjugate Therapy of Hematologic Malignancies
The limited success of first-generation ADCs developed in the early s informed strategies to bring second-generation ADCs to the market, which have higher levels of cytotoxic drug conjugation, lower levels of naked antibodies and more-stable linkers between the drug and the antibody. Furthermore, lessons learned during the past decade are now being used in the development of third-generation ADCs. In this review, I have discussed the current strategies for developing ADCs against hematological malignancy and other cancers. This included selection of target antigens as well as suitable cytotoxic drugs; the design of optimized linkers; preclinical development; clinical trials and toxicity issues.
The selection and engineering of antibodies for site-specific drug conjugation, which will result in higher homogeneity and increased stability, as well as the quest for new conjugation chemistries and mechanisms of action, are priorities in future ADC research and development.
One important issue that may have to be addressed is the development of host resistance to ADCs, similar to mixed drug resistance MDR observed for chemotherapeutic drugs. Lorenzo and co-workers have suggested that the modular nature of the ADC will allow components to be switched and replaced, enabling development of second-generation ADCs that overcome acquired resistance. September , Accessed June 10, Mylotarg gemtuzumab ozogamicin : market withdrawal. FDA press release. Accessed June 9, Interim results. Hematology Oncology. Shah, SA. International Journal of Toxicology, Trail PA.
Encyclopedia of Immunology. PMID Enhancement of the selectivity and antitumor efficacy of a CC analogue through immunoconjugate formation.
Treatment of hematologic malignancies with immunotoxins and antibody-drug conjugates. Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Continuous cultures of fused cells secreting antibody of predefined specificity. A novel antibody-drug conjugate targeting SAIL for the treatment of hematologic malignancies.
Antibody-drug conjugates in hematological malignancies. Mechanisms of Resistance to Antibody-Drug Conjugates. American Society of Clinical Oncology. Mol Cancer Ther Dec;15 12 Antibody-drug conjugates for the treatment of non-Hodgkin's lymphoma: target and linker-drug selection. Brentuximab vedotin SGN in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study.
The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Anti-B4-blocked ricin immunotoxin shows therapeutic efficacy in four different SCID mouse tumor models. Safety was evaluated in patients with relapsed or refractory ALL treated with blinatumomab [ ].
The most common reasons for interruption were neurologic toxicity and CRS. The most common reasons for permanent withdrawal included neurologic toxicity and sepsis. The panel recommended the use of blinatumomab for patients with relapsed or refractory ALL based on level B evidence. These include unconjugated monoclonal antibodies and monoclonal antibodies conjugated with cytotoxins.
An approach to enhance the efficacy of antibody therapy is the use of BiTE antibodies like blinatumomab mentioned on the previous page. By bridging tumor antigens with T cell receptors, these can direct effector T cells to leukemia blasts target antigens. In recent years, different T cell engaging antibody constructs have been developed.
Several phase I and phase II antigen-specific antibody clinical trials are currently in development for the treatment of acute leukemia.
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- Advances in the treatment of hematologic malignancies using immunoconjugates.?
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Epratuzumab, an unconjugated humanized monoclonal antibody, binds to the third extracellular domain of CD The addition of epratuzumab was well tolerated, with a similar toxicity profile to that observed with the re-induction chemotherapy platform regimen alone. While CR rates were not improved compared to historical controls treated with chemotherapy alone, there was a non-significant trend towards improvement in MRD response with the addition of epratuzumab to re-induction chemotherapy.
A multicenter randomized trial compared a pediatric-inspired protocol to the same regimen plus rituximab in patients newly diagnosed with CDpositive Ph-negative B-Cell precursor ALL in the rituximab arm and in the control arm [ ].go to site
Advances in the treatment of hematologic malignancies using immunoconjugates.
Median age was 40 years. Both randomization arms were well balanced for pretreatment characteristics. Ofatumumab is an anti-CD20 antibody that targets a membrane proximal small-loop epitope on the CD20 molecule. Alemtuzumab is a humanized monoclonal antibody directed against the CD52 antigen present on the surface of immune cells. Alemtuzumab has limited activity as single agent in patients with ALL [ ].
The addition of alemtuzumab resulted in reduction of MRD, but it was also associated with viral infections [ ]. Based on these results an expansion phase was completed which may confirm the preliminary results. Inotuzumab ozogamicin is a humanized anti-CD22 antibody conjugated to calicheamicin. In a recent phase 3 trial patients with relapsed or refractory ALL were randomized to inotuzumab ozogamicin or standard of care intensive chemotherapy [ ]. The rate of CR was significantly higher in the inotuzumab ozogamicin group than in the standard-therapy group Among the patients who had CR a higher percentage in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease.
The duration of remission was longer in the inotuzumab ozogamicin group median, 4. In the survival analysis, which included all patients, PFS was significantly longer in the inotuzumab ozogamicin group median, 5. CD33 is a myeloid differentiation antigen that is broadly expressed on AML blasts. However, in gemtuzumab ozogamicin was voluntary withdrawn after a phase 3 trial SWOG S in newly diagnosed AML based showed a trend toward an increased mortality in the gemtuzumab ozogamicin arm [ ]. A recent meta-analysis from five randomized controlled trials incorporating gemtuzumab ozogamicin demonstrated a significant survival benefit for patients with favorable and intermediate cytogenetic characteristics suggesting of reassessing the status of gemtuzumab ozogamicin [ ].
An early report from a phase I clinical trial of 25 AML high-risk patients who achieved CR indicated that the antibody was safe and well tolerated [ ]. Surface expression and inhibitory functions of checkpoint inhibitors are up-regulated in T cells present in the tumor microenvironment.
While the presence of these inhibitory receptors on T cells is physiologically necessary to regulate cellular activation, their overexpression in disease leads to dysfunction of T cells and other immune effector cells [ — ].
In the setting of cancer, chronic overexpression of checkpoint molecules results in T cell dysfunction and impairs anti-tumor immunity. The PD-1 receptor biology, expression of PD-1 on the surface of activated immune cells and its ligands, PD-L1 and PD-L2, on leukemic blasts and functional consequences of antibody-based or pharmacologic blockade of PD-1 are under investigation in acute leukemia [ — ].
PD-1 blockade can restore anti-leukemia T cell functions and thus may offer therapeutic advantages in acute leukemia. The panel was in consensus that there is preclinical rationale for consideration of clinical trials for immune-checkpoint blockade in acute leukemia. The panel identified the following clinical settings for evaluation of immune-checkpoint blockade in acute leukemia: patients with MRD, high-risk patients, and elderly patients. Adoptive transfer of T cells engineered to express a CAR has emerged as a powerful immunotherapy.
As described above, CAR are synthetic molecules consisting of an extracellular antigen-binding domain fused via a spacer region to intracellular signaling domains that are capable of activating T cells. CARs engage molecular structures independent of antigen processing by the target cell and independent of MHC [ , ].