Inotuzumab ozogamicin in clinical development for acute lymphoblastic leukemia and non-Hodgkin lymphoma

Aujla, Amandeep; Aujla, Ravijot; Liu, Delong

doi:10.1186/s40364-019-0160-4

Cited by 24 publications

(17 citation statements)

References 92 publications

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“…ADC composes of three essential components: a mAb that recognizes a tumor-specific antigen, a cytotoxic molecule often referred to as payload, and a chemical linker that connects the mAb and payload [78][79][80][81]. Upon binding to the corresponding antigen on the surface of tumor cells, ADC is internalized first and the linker is hydrolyzed inside of the lysosomes or endosomes, releasing the payloads that lead to cell death by damaging DNA or impeding microtubule assembly.…”

Section: Bcma Antibody-drug Conjugate (Adc)mentioning

confidence: 99%

BCMA-targeted immunotherapy for multiple myeloma

2020

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B cell maturation antigen (BCMA) is a novel treatment target for multiple myeloma (MM) due to its highly selective expression in malignant plasma cells (PCs). Multiple BCMA-targeted therapeutics, including antibody-drug conjugates (ADC), chimeric antigen receptor (CAR)-T cells, and bispecific T cell engagers (BiTE), have achieved remarkable clinical response in patients with relapsed and refractory MM. Belantamab mafodotin-blmf (GSK2857916), a BCMA-targeted ADC, has just been approved for highly refractory MM. In this article, we summarized the molecular and physiological properties of BCMA as well as BCMA-targeted immunotherapeutic agents in different stages of clinical development.

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Section: Bcma Antibody-drug Conjugate (Adc)mentioning

confidence: 99%

BCMA-targeted immunotherapy for multiple myeloma

2020

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“…Antibody-drug conjugates (ADCs) are complex molecules composed of antibodies conjugated with cytotoxic payloads via chemical linkers. The well-described mechanism of action for ADC drugs includes [68,71,72] (1) binding of the mAb to the target in tumor cells; (2) internalizing the ADC into the cells through receptormediated endocytosis; (3) releasing the cytotoxic payload from the internalized ADC to kill the target cells [73]. The critical requirements for ADC drugs include unique expression of the targets on tumor cells but no or minimal expression in normal tissues, stable linkers that can only be cut inside of the target cells, and targets able to internalize upon antibody binding.…”

Section: Selection Of Igg Subclass Format In Adc Drug Developmentmentioning

confidence: 99%

How to select IgG subclasses in developing anti-tumor therapeutic antibodies

2020

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The intact antibody of human immunoglobulin (IgG) is composed of the fragment for antigen binding (Fab) and the crystallizable fragment (Fc) for binding of Fcγ receptors. Among the four subclasses of human IgG (IgG1, IgG2, IgG3, IgG4), which differ in their constant regions, particularly in their hinges and CH2 domains, IgG1 has the highest FcγRbinding affinity, followed by IgG3, IgG2, and IgG4. As a result, different subclasses have different effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Fcγ receptors include six subtypes (FcγRI, FcγRIIA, FcγRIIB, FcγRIIC, FcγRIIIA, FcγRIIIB) which differ in cellular distribution, binding affinity to Fc, and the resulting biological activity. Therefore, when developing anti-tumor therapeutic antibodies, including single-targeted antibodies, bi-specific antibodies (BsAbs), and antibody-drug conjugates (ADCs), many factors, such as target biology, cellular distribution of the targets, the environments of particular tumor types, as well as the proposed mechanism of action (MOA), must be taken into consideration. This review outlines fundamental strategies that are required to select IgG subclasses in developing anti-tumor therapeutic antibodies.

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“…New advances in the design and manufacture of MoAbs, Bispecific T cell engagers (BiTEs), and antibody-drug conjugates (ADCs) make the antibody-directed agents more powerful with less toxicities [1,[10][11][12]. Blinatumomab as the first approved CD19-targeted BiTE is being studied for induction therapy for elderly patients with acute lymphoblastic leukemia (ALL) and for incorporation into the regimens containing the CD22-targeted ADC, inotuzumab ozogamicin, in an attempt to enhance efficacy and reduce toxicities [13][14][15]. ADCs targeting CD30, CD33, or CD79 have been approved for clinical therapy of lymphomas and AML with the appropriate targets [16][17][18].…”

Section: Antibodies: More On-target and Less Off-tumor Effectsmentioning

confidence: 99%

CAR-T “the living drugs”, immune checkpoint inhibitors, and precision medicine: a new era of cancer therapy

Liu

2019

J Hematol Oncol

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New advances in the design and manufacture of monoclonal antibodies, bispecific T cell engagers, and antibodydrug conjugates make the antibody-directed agents more powerful with less toxicities. Small molecule inhibitors are routinely used now as oral targeted agents for multiple cancers. The discoveries of PD1 and PD-L1 as negative immune checkpoints for T cells have led to the revolution of modern cancer immunotherapy. Multiple agents targeting PD1, PD-L1, or CTLA-4 are widely applied as immune checkpoint inhibitors (ICIs) which alleviate the suppression of immune regulatory machineries and lead to immunoablation of once highly refractory cancers such as stage IV lung cancer. Tisagenlecleucel and axicabtagene ciloleucel are the two approved CD19-targeted chimeric antigen receptor (CAR) T cell products. Several CART cell platforms targeting B cell maturation antigen (BCMA) are under active clinical trials for refractory and/or relapsed multiple myeloma. Still more targets such as CLL-1, EGFR, NKG2D and mesothelin are being directed in CART cell trials for leukemia and solid tumors. Increasing numbers of novel agents are being studied to target cancer-intrinsic oncogenic pathways as well as immune checkpoints. One such an example is targeting CD47 on macrophages which represents a "do-not-eat-me" immune checkpoint. Fueling the current excitement of cancer medicine includes also TCR-T cells, TCR-like antibodies, cancer vaccines and oncolytic viruses.

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Inotuzumab ozogamicin in clinical development for acute lymphoblastic leukemia and non-Hodgkin lymphoma

Cited by 24 publications

References 92 publications

BCMA-targeted immunotherapy for multiple myeloma

BCMA-targeted immunotherapy for multiple myeloma

How to select IgG subclasses in developing anti-tumor therapeutic antibodies

CAR-T “the living drugs”, immune checkpoint inhibitors, and precision medicine: a new era of cancer therapy

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