Minireview Current Approaches for Absorption, Distribution, Metabolism, and Excretion Characterization of Antibody-Drug Conjugates: An Industry White Paper

ABSTRACT An antibody-drug conjugate (ADC) is a unique therapeutic modality composed of a highly potent drug molecule conjugated to a monoclonal antibody. As the number of ADCs in various stages of nonclinical and clinical development has been increasing, pharmaceutical companies have been exploring diverse approaches to understanding the disposition of ADCs. To identify the key absorption, distribution, metabolism, and excretion (ADME) issues worth examining when developing an ADC and to find optimal scientifically based approaches to evaluate ADC ADME, the International Consortium for Innovation and Quality in Pharmaceutical Development launched an ADC ADME working group in early 2014. This white paper contains observations from the working group and provides an initial framework on issues and approaches to consider when evaluating the ADME of ADCs

The tip of the iceberg: Post caesarean wound dehiscence presenting as abdominal wound sepsis

Introduction: Uterine scar dehiscence can complicate caesarean section with complications like post partum hemorrhage, endomyometritis, localized/generalized peritonitis, and sepsis. Presentation of case: Our patient had abdominal wound infection after LSCS surgery and features of sepsis. The wound infection was actually the presentation of a uterine scar dehiscence and localized peritonitis. Discussion: Incidence of uterine scar dehiscence is around 0.6%. Presentation can be post partum hemorrhage, endomyometritis, and generalized/localized peritonitis. Peritonitis caused by uterine incisional necrosis must be dealt surgically. A high index of suspicion with appropriate investigations can highlight such problems for early treatment and cure with least morbidity especially related to further pregnancies. Conclusion: Uterine scar dehiscence with infection requires high index of suspicion as rare cause for post partum localized/generalized peritonitis with sepsis. Severe abdominal wound infection after caesarean section may be associated with uterine wound dehiscence, which poses a grave risk to the mother in a future pregnancy

Phase 1 study of anti-CD47 monoclonal antibody CC-90002 in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndromes

CC-90002 is an anti-CD47 antibody that inhibits CD47-SIRPα interaction and enables macrophage-mediated killing of tumor cells in hematological cancer cell lines. In this first clinical, phase 1, dose-escalation and -expansion study (CC-90002-AML-001; NCT02641002), we evaluated CC-90002 in patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS). CC-90002 was administered in escalating doses of 0.1-4.0 mg/kg, using a modified 3 + 3 design. Primary endpoints included dose-limiting toxicities (DLTs), non-tolerated dose (NTD), maximum tolerated dose (MTD), and recommended phase 2 dose. Secondary endpoints included preliminary efficacy, pharmacokinetics, and presence/frequency of anti-drug antibodies (ADAs). Between March 2016 and July 2018, 28 patients were enrolled (24 with AML and 4 with MDS) at 6 sites across the USA. As of July 18, 2018, all patients had discontinued, mainly due to death or progressive disease. The most common treatment-emergent adverse events were diarrhea (46.4%), thrombocytopenia (39.3%), febrile neutropenia (35.7%), and aspartate aminotransferase increase (35.7%). Four patients experienced DLTs (1 patient had grade 4 disseminated intravascular coagulation and grade 5 cerebral hemorrhage, 1 had grade 3 purpura, 1 had grade 4 congestive cardiac failure and grade 5 acute respiratory failure, and another had grade 5 sepsis). The NTD and MTD were not reached. No objective responses occurred. CC-90002 serum exposure was dose-dependent. ADAs were present across all doses, and the proportion of ADA-positive patients in cycle 1 increased over time. Despite no unexpected safety findings, the CC-90002-AML-001 study was discontinued in dose escalation for lack of monotherapy activity and evidence of ADAs. However, as other anti-CD47 agents in clinical trials are showing promising early results for AML and MDS, understanding preclinical and clinical differences between individual agents in this class will be of high importance

Current Approaches for ADME Characterization of Antibody-Drug Conjugates: An Industry White Paper Running Title Current Approaches for ADME Characterization of ADCs

Abstract An antibody-drug conjugate (ADC) is a unique therapeutic modality composed of a highly potent drug molecule conjugated to a monoclonal antibody (mAb). As the number of ADCs in various stages of nonclinical and clinical development has been increasing, pharmaceutical companies have been exploring diverse approaches to understanding the disposition of ADCs. In order to identify the key ADME issues worth examining when developing an ADC and to find optimal scientifically-based approaches to evaluate ADC ADME, the International Consortium for Innovation and Quality in Pharmaceutical Development launched an "ADC ADME working group" in early 2014. This White Paper contains observations from the working group and provides an initial framework on issues and approaches to consider when evaluating the ADME of ADCs. DMD # 68049