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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Inotuzumab ozogamicin (Besponsa™) is an antibody-drug conjugate used to treat relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). It consists of a semisynthetic derivative of N-acetyl ɣ-calicheamicin 1, 2-dimethyl hydrazine dichloride (NAc ɣ-calicheamicin DMH), a potent DNA-cleaving agent, covalently linked via an acid-labile 4-(4′-acetylphenoxy) butanoic acid (acetyl butyrate) linker to a humanized monoclonal IgG4 antibody, G544 (Figure 7.33). The linker provides stability at physiologic pH but successfully releases the calicheamicin inside the acidic environment of the lysosomes. Inotuzumab ozogamicin was made through a collaboration by researchers from Celltech and Wyeth, but developed by Pfizer after it acquired Wyeth. Structure of inotuzumab ozogamicin (BesponsaTM) which has an average loading of 5–7 moles of ɣ-calicheamicin payload per mole of antibody (Image from Jani, Darshana & Nowak, John & Chen, Ying & Boni, Joseph & Gorovits, Boris. (2018). Assessment of clinical immunogenicity of inotuzumab ozogamicin in patients with non-Hodgkin lymphoma and acute lymphoblastic leukemia. AAPS Open. 4. 10.1186/s41120-018-0021-5).
Leukaemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Despite the significant improvement in the therapy of ALL, in particular in children, approximately 25% of children and 50%–60% of adults relapse. Second remissions (CR2) can be achieved in most of these patients, but in many cases they are not sustained. Factors associated with a poor outcome after relapse include a shorter length of first remission, bone marrow as the initial site of relapse, older age, T-ALL, BCR-ABL1 and male sex. For patients who relapse more than 2 years after achieving CR, remission may be re-induced with the same drugs that induced the first remission. For primary resistant disease, most specialists use high-dose cytarabine either alone or in combination with an anthracycline. Recent efforts are assessing novel approaches in targeting pathways. The karyopherin exportin1 (XPO1/CRM1) regulates cell proliferation and survival by facilitating nuclear export of several factors, including tumour suppressors, such as p53, p21, FOXO and IκB, and leukaemia-relevant proto-oncogenes, including hnRNP A1, ABL1 and SET. The observation that the expression and activity of XPO1/CRM1 is altered in BCR-ABL1 positive and other poor-risk ALLs, suggests its potential role in pathogenesis.82 Candidate drugs in clinical trials include KPT-330, nelarabine (506U78), immunotoxins/immuno-conjugates such as inotuzumab ozogamicin and a variety of antibody-based therapies, such as blinatumumab, epratuzumab, and alemtuzumab. Nelarabine, a prodrug that is rapidly demethylated to AraG, have substantial clinical activity in T-ALL in first relapse and is currently in clinical trials for newly diagnosed patients.83 Antigen-directed immune therapies, such as blinatumomab, a bi-specific monoclonal antibody designed to harness cytotoxic T-cells (CTL) responses to CD19-expressing target B cells, appear to accord some adults patients with MRD-positive B-ALL and relapsed ALL a CR. Patients who express the cytokine receptor CRLF2 appear to benefit from Janus kinase (JAK) and mammalian target of rapamycin (mTOR) inhibitors, probably by virtue of both JAK-STAT and mTOR pathways being involved. It is of some interest that approximately 60% children with DS-ALL, uniquely, express CRLF2 and should receive a trial of either JAK or mTOR inhibitors.84 Two new drugs, clofarabine, a purine analogue discussed earlier, and a liposomal formulation of vincristine sulfate, have recently been licensed in the United States for patients with Ph chromosome-negative ALL in second relapse.85
Factors Affecting the Cancer Immunotherapeutic Efficacy of T Cell Bispecific Antibodies and Strategies for Improvement
Published in Immunological Investigations, 2022
Meixiao Long, Alice S. Mims, Zihai Li
For some malignancies, targeted therapy or immunotherapy could provide an alternative approach to achieve significant debulking and even remission with minimal negative impact on T-cell number and function. Inotuzumab ozogamicin is an antibody‒drug conjugate targeting CD22 that is expressed by most acute lymphoblastic leukemia (ALL). Sequential treatment with the single agent inotuzumab followed by blinatumomab has been demonstrated to have good efficacy and safety profiles in clinical trials with ALL patients (Ueda et al. 2022). Similarly, tyrosine kinase inhibitors have been used for prephase debulking for Ph-positive ALL before initiating treatment with blinatumomab in several clinical trials (Advani et al. 2021; Short et al. 2021). For multiple myeloma patients, there are more options for debulking without harming T-cell immunity. CD38 antibodies, proteasome inhibitors and immunomodulatory drugs (IMiDs) are all standard treatment options. Proteosome inhibitors and CD38 antibodies have a much lower impact on T-cell immunity than cytotoxic chemotherapies. IMiDs such as lenalidomide and pomalidomide have been found to enhance the potency of BCMA BsAbs in multiple myeloma preclinical models (Ghobadi et al. 2020). Thus, myeloma patients can achieve significant cytoreduction and even complete remission without significantly compromising T-cell immunity. Currently, there are multiple ongoing clinical trials combining IMiDs and/or proteasome inhibitors with BCMA BsAb.
The emerging role of antibody-drug conjugates in urothelial carcinoma
Published in Expert Review of Anticancer Therapy, 2020
Michael Lattanzi, Jonathan E. Rosenberg
ADCs are also beginning to take on a more prominent role in the management of lymphoid malignancies. Brentuximab vedotin is a CD30-specific ADC which is currently approved for the treatment of Hodgkin’s lymphoma, anaplastic large cell lymphoma, and peripheral T cell lymphoma. Structurally, brentuximab vedotin is an anti-CD30 monoclonal antibody conjugated to the anti-microtubule agent monomethyl auristatin E (MMAE) via a protease-cleavable linker [43]. On the basis of high response rates in early phase clinical trials [44–46], brentuximab vedotin was approved by the US FDA in 2011 and continues to be investigated for expanded use among other CD30-positive lymphomas. More recently, inotuzumab ozogamicin was approved by the FDA in 2017 for the treatment of relapsed or refractory B cell precursor acute lymphoblastic leukemia (B-ALL). Approval was based on a randomized phase III trial of inotuzumab ozogamicin versus standard intensive chemotherapy which found a clinically and statistically significant increase in complete response rate of 80.7% with inotuzumab ozogamicin versus just 29.4% with standard therapy [11]. Finally, polatuzumab vedotin, a CD79b targeted ADC, was shown in a randomized phase II study to confer an increased response rate (40% versus 18%) when added to standard bendamustine and rituximab for the treatment of relapsed or refractory diffuse large B cell lymphoma, and was granted accelerated approval in 2019 [47].
Survival after stem-cell transplant in pediatric and young-adult patients with relapsed and refractory B-cell acute lymphoblastic leukemia
Published in Current Medical Research and Opinion, 2018
Alessandro Crotta, Jie Zhang, Christopher Keir
In addition to CAR T-cell therapies, several new strategies for the treatment of r/r disease are in late-stage development. Blinatumomab, a bispecific T-cell engager monoclonal antibody that facilitates T-cell targeting of CD19, was approved by the US Food and Drug Administration in 201426. Blinatumomab is in phase 3 trials as consolidation therapy in pediatric patients with relapsed ALL (NCT02393859 and NCT02101853) as well as maintenance therapy to prevent recurrence after SCT in adults with B-ALL (NCT02807883). Inotuzumab ozogamicin is an antibody–drug conjugate that couples a potent cytotoxic agent, N-acetyl-γ-calicheamicin, with an anti-CD22 monoclonal antibody. Inotuzumab ozogamicin has shown promising early clinical results and is currently in phase 2 trials27. It should be noted that the CIBMTR registry data regarding treatments received during the follow-up period are not available. Thus, it is possible that some patients went on to receive treatments that could have included CAR T-cell therapies or blinatumomab. Notably, however, there is little overlap between the interval of the transplant years in the database (2009–2013) and the availability of CAR T-cell therapies (approximately 2011) or blinatumomab (approximately 2012).