Delving into the Latest Updates on Pinatuzumab vedotin with Synapse

Overview

Basic Info

Drug Type

Antibody drug conjugate (ADC)

Synonyms

Anti-CD22-ADC, Anti-CD22-MCC-DM1, DCDT 2980S antibody-drug conjugate

+ [8]

Target

CD22 x Tubulin

Mechanism

CD22 inhibitors(CD22 inhibitors), Tubulin inhibitors

Therapeutic Areas

NeoplasmsImmune System DiseasesHemic and Lymphatic Diseases

Active Indication-

Inactive Indication

B-cell lymphoma refractoryChronic Lymphocytic LeukemiaDiffuse Large B-Cell Lymphoma+ [1]

Originator Organization

Genentech, Inc.

Active Organization-

Inactive Organization

Genentech, Inc.

Drug Highest PhasePendingPhase 1/2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC39H67N5O7

InChIKeyDASWEROEPLKSEI-UIJRFTGLSA-N

CAS Registry474645-27-7

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Sequence Code 204327H

Source: *****

Sequence Code 116255L

Source: *****

A Randomized, Open-Label, Multicenter, Phase II Trial Evaluating the Safety and Activity of Pinatuzumab Vedotin (DCDT2980S) in Combination With Rituximab or Polatuzumab Vedotin (DCDS4501A) in Combination With Rituximab and a Non-Randomized Phase Ib/II Evaluation of Polatuzumab Vedotin in Combination With Obinutuzumab in Patients With Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma

This multicenter, open-label study will evaluate the safety and efficacy of pinatuzumab vedotin (DCDT2980S) or polatuzumab vedotin (DCDS4501A) in combination with rituximab (RTX), as well as of polatuzumab vedotin in combination with obinutuzumab in participants with relapsed or refractory (r/r) follicular lymphoma (FL) and r/r diffuse large B-cell lymphoma (DLBCL).

Start Date27 Sep 2012

Sponsor / Collaborator

Genentech, Inc.

NCT01209130

/ CompletedPhase 1

An Open-Label, Multicenter, Phase I Trial of the Safety and Pharmacokinetics of Escalating Doses of DCDT2980S in Patients With Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia And DCDT2980S in Combination With Rituximab in Patients With Relapsed or Refractory B-Cell Non Hodgkin's Lymphoma

This is a Phase I, multicenter, open-label, dose-escalation study of DCDT2980S administered by intravenous (IV) infusion to patients with relapsed or refractory hematologic malignancies. In addition, at selected sites, DCDT2980S will be studied in combination with rituximab.

Start Date01 Oct 2010

Sponsor / Collaborator

Genentech, Inc.

100 Clinical Results associated with Pinatuzumab vedotin

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100 Translational Medicine associated with Pinatuzumab vedotin

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100 Patents (Medical) associated with Pinatuzumab vedotin

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20

Literatures (Medical) associated with Pinatuzumab vedotin

01 Dec 2024·Iranian biomedical journal

25th National and 11th International Annual Congress on Research and Technology of Iranian Medical Sciences Students, Urmia, Iran, 5-7 September, 2024

Article

Author: Arashkia, Arash ; Abdoli, Shahriyar ; Hamidieh, Amir Ali ; Riyazi Rad, Farhad ; Gholizadeh, Monireh ; Sharifzadeh, Zahra ; Nouri, Mohammad

IntroductionCD22 is a surface antigen predominantly found in cancerous B-cell lineages, making it a significant target for biopharmaceuticals to treat hematologic B-cell malignancies. Biopharmaceuticals, including vaccines, cell and gene therapies, and recombinant protein therapies, have revolutionized medical treatments. Monoclonal antibodies (mAbs)are prominent in this field but face challenges such as stability, aggregation, and post-translational modifications. To address these issues, researchers have developed single-chain variable fragments (scFvs), which are smaller and potentially more stable derivatives of mAbs.Methods and MaterialsAn anti-CD22-scFv was designed and synthesized for expression in Escherichia coli. The protein was purified using immobilized metal affinity chromatography (IMAC) based on column refolding and purification and native purification. We optimized expression conditions, including post-induction temperature, post-induction time, and Isopropyl β-D-1-thiogalactopyranoside (IPTG) concentration, to maximize the soluble protein yield. The binding capacity of the hybrid- and native-purified proteins to CD22+ Raji and CD22-K562 cells was assessed using flow cytometry. The efficacy of anti-CD22-scFv in inhibiting the proliferation of CD22+ Raji cells was evaluated using the MTT assay.ResultsThe anti-CD22-scFv protein was successfully expressed in the Rosetta (DE3) strain using the pET-28a+ expression vector but not in the Rosetta-gami 2 strain. Hybrid purification followed by 12% SDS-PAGE and Coomassie brilliant blue staining confirmed the protein expression. Initial solubility tests indicated that the anti-CD22-scFv protein was insoluble. Optimizing the conditions to an IPTG concentration of 0.5 mM, a post-induction temperature of 25 °C, and an eight-hour post-induction time yielded higher solubility. Native-purified and hybrid-purified anti-CD22-scFvs showed binding affinities of 91.4% and 84% to CD22+ Raji cells, respectively. The anti-CD22-scFv significantly reduced the proliferation of CD22+ Raji cells.Conclusion and DiscussionThis study demonstrates the effectiveness of a one-step IMAC-based purification method for isolating anti-CD22-scFv protein from recombinant E. coli, combining the purification and refolding into a single, cost-effective step. Optimization of the environmental parameters, including expression strain, post-induction temperature, post-induction time, and IPTG concentration, significantly improved the protein yield and solubility. The anti-CD22-scFv shows promising potential in targeting and reducing the proliferation of CD22+ tumor cells, highlighting its therapeutic potential for B-cell malignancies.

13 Sep 2024·Xenobiotica

Monomethyl auristatin E (MMAE), a payload for multiple antibody drug conjugates (ADCs), demonstrates differential red blood cell partitioning across human and animal species

Article

Author: Yip, Victor ; Shen, Ben-Quan ; Leipold, Doug ; Saad, Ola M. ; Li, Chunze ; Kamath, Amrita

Background: Monomethyl auristatin E (MMAE) has been used as a payload for several Food and Drug Administration (FDA) approved antibody-drug conjugates (ADCs). It is known that MMAE is released from the ADC following binding, internalisation and proteolytic degradation in target tissues. A striking discrepancy in systemic MMAE levels has been observed across species with 50-fold higher MMAE levels in human than that in rodents when normalised by ADC dose with unknown mechanism.Hypothesis and purpose: Multiple factors could affect systemic MMAE levels such as production and elimination of unconjugated MMAE following ADC dosing. In this study, we have explored whether MMAE displays differential red blood cell (RBC) partitioning across species that may contribute to the different MMAE levels seen between human and animals.Experiments: To determine MMAE RBC partitioning, tritium labelled MMAE ([³H]-MMAE) was incubated in whole blood from mice, rats, monkeys and humans in vitro, then RBC partitioning was determined and compared across species. To test whether MMAE released from the ADC would show any difference in RBC partitioning, pinatuzumab vedotin or polatuzumab vedotin was administered to mice, rats, and monkeys. MMAE levels were measured in both blood and plasma, and the ratios of MMAE levels were calculated as blood-to-plasma ratio (in vivo RBC partitioning).Results: Our in vitro data showed that unconjugated MMAE has a species-dependent RBC partitioning with strong RBC partitioning in mouse, rat, followed by monkey blood, whereas minimal RBC partitioning was seen in human blood. Incubation of 2 nM of MMAE in mouse blood resulted in a blood-to-plasma ratio of 11.8 ± 0.291, followed by rat, monkey, and human at 2.36 ± 0.0825, 1.57 ± 0.0250, and 0.976 ± 0.0620, respectively. MMAE RBC partitioning is also concentration-dependent, with an inverse relationship between RBC partitioning and MMAE concentration (higher RBC partitioning at lower concentration). In vivo dosing of pinatuzumab vedotin in mouse displayed systemic MMAE at about a 5-fold higher blood concentration compared to plasma concentration once MMAE reached a pseudo-equilibrium, while systemic MMAE from blood and plasma concentration showed a 1.65-fold difference in rat.Implication and conclusion: These data demonstrated that MMAE has a distinct RBC partitioning across different species, which may contribute to, at least in part, to the differential in the systemic MMAE levels observed in vivo between preclinical and clinical studies. These findings highlight the importance of fully characterising the ADME properties of both the ADC and its payload, to enable better translation from animals to human for ADC development.

01 Feb 2021·Molecular Cancer TherapeuticsQ2 · MEDICINE

An Anti–CD22-seco-CBI-Dimer Antibody–Drug Conjugate (ADC) for the Treatment of Non-Hodgkin Lymphoma That Provides a Longer Duration of Response than Auristatin-Based ADCs in Preclinical Models

Q2 · MEDICINE

Article

Author: Zhong, Fiona ; Leipold, Douglas ; Yu, Shang-Fan ; Pillow, Thomas ; Zheng, Bing ; Lee, Donna W. ; Dragovich, Peter S. ; Hong, Kyu ; Sadowsky, Jack D. ; Schutten, Melissa M. ; Yan, Peter ; Polson, Andrew G. ; Carrasco-Triguero, Montserrat ; Rowntree, Rebecca K. ; del Rosario, Geoffrey ; Booler, Helen

AbstractWe are interested in developing a second generation of antibody–drug conjugates (ADCs) for the treatment of non-Hodgkin lymphoma (NHL) that could provide a longer duration of response and be more effective in indolent NHL than the microtubule-inhibiting ADCs pinatuzumab vedotin [anti–CD22-vc-monomethyl auristatin E (MMAE)] and polatuzumab vedotin (anti–CD79b-vc-MMAE). Pinatuzumab vedotin (anti–CD22-vc-MMAE) and polatuzumab vedotin (anti–CD79b-vc-MMAE) are ADCs that contain the microtubule inhibitor MMAE. Clinical trial data suggest that these ADCs have promising efficacy for the treatment of NHL; however, some patients do not respond or become resistant to the ADCs. We tested an anti-CD22 ADC with a seco-CBI-dimer payload, thio-Hu anti–CD22-(LC:K149C)-SN36248, and compared it with pinatuzumab vedotin for its efficacy and duration of response in xenograft models and its ability to deplete normal B cells in cynomolgus monkeys. We found that anti–CD22-(LC:K149C)-SN36248 was effective in xenograft models resistant to pinatuzumab vedotin, gave a longer duration of response, had a different mechanism of resistance, and was able to deplete normal B cells better than pinatuzumab vedotin. These studies provide evidence that anti–CD22-(LC:K149C)-SN36248 has the potential for longer duration of response and more efficacy in indolent NHL than MMAE ADCs and may provide the opportunity to improve outcomes for patients with NHL.

100 Deals associated with Pinatuzumab vedotin

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External Link

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
B-cell lymphoma refractory	Phase 2	FR	Genentech, Inc.	27 Sep 2012
B-cell lymphoma refractory	Phase 2	IT	Genentech, Inc.	27 Sep 2012
B-cell lymphoma refractory	Phase 2	DE	Genentech, Inc.	27 Sep 2012
B-cell lymphoma refractory	Phase 2	US	Genentech, Inc.	27 Sep 2012
B-cell lymphoma refractory	Phase 2	CA	Genentech, Inc.	27 Sep 2012
B-cell lymphoma refractory	Phase 2	NL	Genentech, Inc.	27 Sep 2012
Refractory Follicular Lymphoma	Phase 2	US	Genentech, Inc.	27 Sep 2012
Refractory Follicular Lymphoma	Phase 2	CA	Genentech, Inc.	27 Sep 2012
Refractory Follicular Lymphoma	Phase 2	NL	Genentech, Inc.	27 Sep 2012
Refractory Follicular Lymphoma	Phase 2	IT	Genentech, Inc.	27 Sep 2012

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01691898 (ROMULUS, Pubmed \| Lancet Haematol) Manual	Phase 2	Non-Hodgkin Lymphoma	41	Polatuzumab Vedotin+Rituximab (R-pola)	(dlnmenncyy) = bzbgjxgyrn fakzoagoth (ucfahqpcbh, 23 - 68) View more	Positive	01 May 2019
NCT01691898 (ROMULUS, Pubmed \| Lancet Haematol) Manual	Phase 2	Non-Hodgkin Lymphoma	41	pinatuzumab vedotin+Rituximab (R-pina)	(dnjhcuanyx) = wfbfjbkgbi lsptgtqevi (ovmrmvyteo ) View more	Positive	01 May 2019
NCT01209130 (Pubmed \| Clin Cancer Res) Manual	Phase 1	B-Cell Lymphoma	75	pinatuzumab vedotin	(xpkxhbcnoz) = lqgjbprwta ktevdlwczy (qdkcxzjgvf )	Positive	01 Mar 2017