anti-CD20 mAb Research Articles

In Situ Self-Assembly of Antibody-Rhamnose Complex as a Pre-Targeting Strategy for Enhanced Cancer Immunotherapy.

Enhancing the Fc effector functions of monoclonal antibodies (mAbs) is a proven strategy for improving cancer immunotherapy. In this study, we present a novel pre-targeting approach that integrates host-guest chemistry with an antibody-recruiting concept to create mAbs with superior effector functions. Using rituximab (RTX), a clinically approved anti-CD20 mAb, as our model, we modified RTX by conjugating it with adamantane (Ada) derivatives and various polyethylene glycol (PEG) linkers to produce RTX-Ada conjugates. These conjugates effectively formed RTX-rhamnose (Rha) complexes in situ through self-assembly, driven by host-guest interactions with Rha-modified β-cyclodextrin. This mechanism successfully redirected endogenous anti-Rha antibodies to target cells, enhancing the availability of Fc domains for improved effector functions, including complement-dependent cytotoxicity (CDC). A structure-activity relationship study indicated that the potency of these in situ complexes was significantly influenced by the length of the PEG linker used; shorter PEG linkers correlated with higher CDC activity. Given the variability in endogenous antibody levels among individuals, this strategy presents a flexible and promising platform for enhancing the efficacy of mAb-based cancer immunotherapy.

Supramolecular assembly of antibody-rhamnose complex to enhance the complement-dependent cytotoxicity for cancer immunotherapy

Enhancing the complement-dependent cytotoxicity (CDC) of monoclonal antibodies (mAbs) has the potential to improve their clinical performance. In this study, we describe an innovative antibody-hapten supramolecular complex strategy to amplify CDC activity. We selected Rituximab (RTX), an approved anti-CD20 mAb, and conjugated it with adamantane (Ada) to generate RTX-Ada. After targeting CD20-positive cells, this conjugate can interact with rhamnose (Rha)-modified β-cyclodextrin via host-guest interaction, in situ forming a supramolecular complex that can recruit anti-Rha antibodies onto CD20-positive cancer cells. This complex provides a larger number of Fc domains for complement system activation, leading to enhanced CDC. Our study demonstrates the potential of antibody-based supramolecular complexes for cancer immunotherapy, offering a promising approach to improve the efficacy of mAb-based cancer treatments.

When Chinese patients with plasma cell disorders encountered the nationwide Omicron outbreak (December 2022): a real-world multicenter and multiregional study.

This study aims to assess the impact of the nationwide Omicron outbreak in December 2022 on Chinese patients with plasma cell disorders (PCD), focusing on the clinical characteristics of PCD patients with COVID-19 and the risk factors contributing to adverse clinical courses (severity and hospitalization) and outcomes. A multicenter retrospective study was performed from December 1, 2022, to January 19, 2023. The study population includes 404 PCD patients, divided into a COVID-19 group (n = 342) and an uninfected group (n = 62). The frequency of COVID-19 infection was 84.7% (342/404), and 16.4% (56/342) were severe COVID-19. Among the 277 patients with complete follow-up, 2 deaths (0.7%) were reported, while 231 (83.4%) recovered from COVID-19. Age > 65 (P = 0.02) and prior anti-CD38 monoclonal antibody (mAb) treatment within six months (P = 0.03) were independent risk factors for severe infection. Additionally, previous chimeric antigen receptor T-cell (CAR-T) therapy within six months was correlated with a higher risk of hospitalization (P = 0.04) and prolonged recovery time (P = 0.03). No significant protective effect of vaccination on infection or severe infection was observed (P > 0.05). The latest Omicron outbreak results in higher rates of severe infection and mortality in PCD patients compared with the general population in China, highlighting the need to protect this vulnerable population during the pandemic. Recent use of anti-CD38 mAb and CAR-T therapy are associated with poorer clinical courses and outcomes of PCD patients with COVID-19.

Challenges in Diagnosis of COVID-19 Pneumonia under Ocrelizumab and De-Risking Strategies in Multiple Sclerosis—The Elephant Is (Still) in the Room

Severe SARS-CoV-2 infections may still be observed in people bearing risk factors, such as the use of anti-CD20 monoclonal antibodies (mAbs), which are adopted in several autoimmune disorders including multiple sclerosis (MS). COVID-19 diagnosis is routinely based on nasopharyngeal swab testing, but suboptimal sensitivity for SARS-CoV-2 detection compared to bronchoalveolar lavage (BAL) may lead to misdiagnosis in some cases. Such diagnostic issues were described in a few MS patients receiving anti-CD20 mAbs, including middle-aged people and lacking information on subsequent MS therapeutic management, a debated topic as no evidence-based guidance on de-risking strategies is currently available. Here, we report the case of a young MS patient who developed severe COVID-19 pneumonia under treatment with the anti-CD20 mAb ocrelizumab, and who was finally diagnosed with SARS-CoV-2 by BAL despite repeatedly negative nasopharyngeal swabs. Ocrelizumab was then discontinued, and treatment with a sphingosine-1 phosphate receptor modulator was started, followed by maintenance of clinical and radiological MS stability. Challenges in diagnosing COVID-19 pneumonia in people without risk factors other than immunomodulatory treatment are hence discussed, as well as potential strategies for de-risking MS therapies. The latter topic is increasingly debated based on raising concerns for potential long-term safety issues of high-efficacy treatments, including anti-CD20 mAbs.

Belantamab mafodotin, pomalidomide, and dexamethasone for triple class exposed/refractory relapsed multiple myeloma: a subgroup analysis of the ALGONQUIN trial

Given the early use of triplet and quadruplet regimens, most patients with multiple myeloma (MM) will be exposed and/or refractory to PIs, IMiDs, and anti-CD38 mAbs after first- or second-line treatment. Effective treatment for this group of triple class exposed/refractory (TCE/R) patients is crucial. Here we present a post-hoc subgroup analysis of TCE/R patients treated on the ALGONQUIN study of belantamab mafodotin plus pomalidomide-dexamethasone (belamaf-Pd) for relapsed MM. Of the 99 patients treated on the ALGONQUIN study, 69 were TCE and 56 were TCR and were included in this analysis. Patients had a median of three prior lines of therapy. The ORR was 86.4% in TCE patients and 84.9% in TCR patients, with ≥ very good partial response rates of 64% and 68% respectively. The median progression free survival was 18.3 months in TCE patients and 19.6 months in TCR patients, with overall survival not yet reached and 34.4 months, respectively for TCE and TCR patients. No new safety signals were identified. The most common Grade ≥ 3 AEs were keratopathy (48%), decreased visual acuity (42%), neutropenia (36%), thrombocytopenia (27%), and infection (25%). In this subgroup analysis of the ALGONQUIN study, patients with TCE/TCR disease treated with belamaf-Pd achieved high clinical response rates with durable remissions, comparable to other novel therapeutics in this space.

Phase 1 Trials of Gatralimab, a Next-Generation Humanized Anti-CD52 Monoclonal Antibody, in Participants with Progressive Multiple Sclerosis.

Lymphocyte depletion via anti-CD52 monoclonal antibody (mAb) therapy is an effective treatment strategy for relapsing-remitting multiple sclerosis (MS) but is associated with infusion/injection-associated reactions (IARs) and autoimmune-related adverse events (AEs). Gatralimab is a next-generation humanized anti-CD52 mAb. Two first-in-human trials were conducted in participants with progressive MS to assess the pharmacodynamics, pharmacokinetics, and safety of gatralimab administered via subcutaneous (SC) and intravenous (IV) routes, and to determine the effect of different comedication regimes on IARs to SC gatralimab. A Phase 1 trial (NCT02282826) included double-blind, placebo-controlled sequential ascending single IV (1, 3.5, and 12mg) and SC (12, 36, and 60mg) dose groups. A Phase 1b trial (NCT02977533) involved five groups who received SC gatralimab (36, 48, or 60mg) and different comedications. A long-term safety (LTS) study (NCT02313285) examined safety and pharmacodynamics over 4years. Gatralimab produced depletion of lymphocytes (dose-dependently) and CD4+ regulatory T cells, with partial repopulation to normal values by approximately 12months. Peak serum gatralimab concentrations followed dose-proportionality and were delayed by 6.0-7.5days following SC administration. Treatment-emergent AEs, including IARs, were reported for most participants but were generally of mild or moderate severity, and treatment-emergent serious AEs were mostly MS-related. Methylprednisolone and antihistamine comedications were associated with reduced incidence of fevers and skin and subcutaneous tissue AEs, respectively. During the LTS study, one participant (3.0%) experienced an autoimmune-related AE (Basedow's disease), and subsequently died from pulmonary sepsis deemed unrelated to gatralimab by the investigator. These data show that gatralimab achieves the desired pharmacodynamic effect of lymphocyte depletion followed by repopulation, and has an acceptable safety profile, including low risk of non-MS autoimmunity. Although gatralimab is no longer in development for MS, insights from these trials may inform the development of comedication regimes of future anti-CD52 mAbs and subcutaneous formulations of other lymphocyte-depleting mAbs. NCT02282826, NCT02977533, NCT02313285.

COVID-19 vaccination in patients with classic and variant hairy cell leukemia

AbstractPatients with the B-cell malignancy hairy cell leukemia (HCL) and the poorer-prognosis variant HCLv often receive anti-CD20 monoclonal antibodies (mAbs), which kill normal B cells, impairing humoral immunity. We measured COVID-19 antibodies after doses of COVID-19 vaccine in patients with HCL (n = 415) and HCLv (n = 32). After the second COVID-19 vaccine dose, spike antibody level most strongly correlated with normal B-cell levels (r = 0.365, P < .0001), followed by CD4+ T-cell count (r = 0.244, P = .0002), and was less related to immunoglobulin G level (r = 0.101, P = .14). Spike antibody also correlated with normal B cells after the third to fifth vaccine doses and with CD4+ count after the third dose. Normal B-cells were undetectable in 87% of patients within 6 months after the last dose of anti-CD20 mAb and were lower than in patients at 6 to 12 months (P = .0003), which, in turn, were lower than at 12 to 18 months (P = .0002). Infection with COVID-19 became more common after use of the third vaccine dose; spike antibody levels were higher in patients with prior infection (positive vs negative nucleocapsid antibodies; P < .0001). Spike antibodies decreased faster after ibrutinib or anti-CD20 mAb. We conclude that decreased levels of normal B cells in patients with HCL/HCLv, due to disease and/or anti-CD20 therapy, are associated with lower COVID-19 vaccination efficiency and such patients may not respond well to vaccines. The associated studies were registered at www.ClinicalTrials.gov as #NCT01087333 (HCL/HCLv) and #NCT04362865 (COVID-19).

CD38-CAR human NK cells in combination with ATRA enhance cytotoxicity against CD38-expressing hematologic malignancies

AbstractCD38 is a metabolically active enzyme broadly expressed on the surface of normal and malignant hematologic cells. It has been targeted clinically with anti-CD38 monoclonal antibodies (mAbs), for which efficacy may be limited by natural killer (NK)–cell fratricide. Isatuximab is an anti-CD38 mAb that uniquely inhibits CD38 metabolic activity. Here, we used CRISPR/adeno-associated virus (AAV) to generate fratricide–resistant and metabolically–enhanced CD38KO/CD38-chimeric antigen receptor (CAR) NK cells using 2 isatuximab-based CD38 single-chain variable fragments (scFvs; reversing heavy and light chain orientation) on the same CD8α/4-1BB/CD3ζ base, and we demonstrate their activity against a range of CD38+ hematologic malignancies (acute myeloid leukemia, multiple myeloma, Burkitt lymphoma, and T-cell leukemia/lymphoma). The cytotoxicity of the CAR NK cells was enhanced by upregulating CD38 expression on the malignant targets with all-trans retinoic acid (ATRA). By generating CD38KO/CD38-CAR T cells using the same engineering approach, we show that the CAR NK cells had higher cytotoxicity than CAR T cells against all hematologic tumor targets. Additionally, AAVS1KO/CD38-CAR NK cells were capable of targeting CD38 without experiencing fratricide and have a similar enhanced metabolic activity via the inhibitory activity of the cis-acting isatuximab-based scFv. Finally, we report fratricide-resistant CD38-CAR NK cells with enhanced metabolism and cytotoxicity toward CD38+ hematologic malignancies, further increased by combination treatment with ATRA.

211At-Labeled Anti-CD45 Antibody as a Nonmyeloablative Conditioning for Canine DLA-Haploidentical Stem Cell Transplantation.

The α-emitter 211At deposits a high amount of energy within a few cell diameters, resulting in irreparable DNA double-strand breaks while minimizing off-target toxicity. We investigated the use of the 211At-labeled anti-CD45 monoclonal antibody (mAb) 211At-CD45-B10 as a nonmyeloablative conditioning regimen for dog-leukocyte-antigen-haploidentical hematopoietic cell transplantation. Methods: Seventeen healthy dogs were injected with either a 0.50 (n = 14) or 0.75 (n = 3) mg/kg dose of anti-CD45 mAb labeled with 211At (8.436-23.199 MBq [0.228-0.627 mCi/kg]) on day -3. Peripheral blood stem cells from dog-leukocyte-antigen-haploidentical donors were given on day 0. Peripheral blood chimerism was calculated by polymerase chain reaction assays, and blood clearance of the radioimmunoconjugate was studied using enzyme-linked immunosorbent assay and radioactivity measurements of serial blood samples. Results: All dogs achieved donor chimerism by day 28 (range, 27%-100%). The hematopoietic engraftment rate was 100%, though engraftment durability was variable. No difference in absorbed dose to blood was seen for the 2 mAb dosing levels studied. Neutropenia (0-29 cells/μL), lymphocytopenia (36-130 cells/μL), and thrombocytopenia (1.5-9 × 103/μL) with prompt recovery were observed. The main adverse nonhematologic event related to 211At-CD45-B10 was mild reversible transaminitis. Graft-versus-host disease was not seen. Twelve of the 17 dogs survived over 30 d, with donor chimerism ranging from 3% to 99%. Conclusion: The results suggest that nonmyeloablative conditioning with 211At-CD45-B10 could be used in haploidentical hematopoietic cell transplantation though with variable engraftment.

An open-label, first-in-human, single agent, dose escalation study for the evaluation of safety and efficacy of SAR442085 in patients with relapsed or refractory multiple myeloma.

Cluster of differentiation 38 (CD38) is a key target on multiple myeloma (MM) cells. This multi-centre, Phase 1, single-agent study (NCT04000282) investigated SAR442085, a novel fragment crystallisable (Fc)-modified anti-CD38 monoclonal antibody (mAb), with enhanced affinity towards Fc-gamma receptor on effector cells in patients with relapsed and/or refractory (RR) MM. This study comprised two parts: Part-A (dose-escalation involving anti-CD38 mAb pre-treated and naïve patients) and Part-B (dose expansion). Primary endpoints were maximum tolerated dose and recommended Phase 2 dose (RP2D). Thirty-seven heavily pre-treated patients were treated in Part A. Part-B (dose-expansion) was not studied. Seven dose-limiting toxicities were reported at DL3, DL5, DL6, and DL7. RP2D was determined to be 5-7·5 mg/kg. Most common treatment-emergent adverse events were infusion-related reactions in 70·3% (26/37) patients. Grade ≥3 thrombocytopenia was reported in 48·6% (18/37). Overall response rate was 70% in anti-CD38 mAb naïve and 4% in anti-CD38 pre-treated patients, with a median progression-free survival of 7·62 (95%CI: 2·858; not calculable) months and 2·79 (95%CI: 1·150; 4·172) months and, respectively. The efficacy of SAR442085 was promising in anti-CD38 mAb naïve patients but did not extend to the larger cohort of anti-CD38 mAb pre-treated patients. This observation, along with transient high-grade thrombocytopenia, could potentially limit its clinical use.

Neonatal B-Cell Levels and Infant Health in Newborns Potentially Exposed to Anti-CD20 Monoclonal Antibodies During Pregnancy or Lactation.

To report CD19+ B-cell counts and possible adverse effects on infants of mothers exposed to anti-CD20 mAbs ≤6 months before/during pregnancy or lactation. We conducted a retrospective study using data from the German nationwide neuroimmunologic pregnancy registry. Inclusion criteria involved infants whose mothers received anti-CD20 mAbs ≤6 months before/during pregnancy or lactation, with ≥1 postnatal CD19+ B-cell count. Main outcomes were absolute and relative CD19+ B-cell counts. Comparison with reference values was performed conservatively in a subgroup with maternal exposure ≤3 months before/during pregnancy. Additional outcomes included pregnancy results, severe infections, and lymphocyte counts. The cohort comprised 49 infants (F:M 25:24) exposed to anti-CD20 mAbs ≤6 months before/during pregnancy or lactation. CD19+ B-cell and lymphocyte counts in 40 infants with maternal exposure ≤3 months before/during pregnancy were comparable with normative values. Only 2 cases of complete CD19+ B-cell depletion occurred after second-trimester and third-trimester ocrelizumab exposure, with repopulation observed within 2 months. Exclusive lactation exposure had no significant effect on infants' absolute CD19+ B-cell counts. Administering anti-CD20 mAbs before or at the pregnancy onset, or during lactation, seems safe without significant impact on infant B-cell development. However, second-trimester or third-trimester exposure can cause CD19+ B-cell depletion due to placental transfer, necessitating monitoring and postponing live vaccines.

Evaluating the Therapeutic Potential of Ublituximab in the Treatment of MS: Design, Development and Place in Therapy.

B cells are critical to the pathogenesis of multiple sclerosis (MS), an autoimmune disease of the central nervous system. B cell depletion using anti-CD20 monoclonal antibodies (mAbs) has proven to be an extremely successful treatment strategy, with profound suppression of both clinical and radiological evidence of focal inflammatory disease. Several anti-CD20 mAbs are now licensed for use in MS, with ublituximab being the latest to gain regulatory approval. The unique properties of each of the anti-CD20 mAb may result in nuanced differences in timing, duration and depth of B cell depletion, with the potential for such differences to have a clinical relevance to both drug efficacy and adverse effects. In this review, we summarize the design, development, and current place in MS therapy for ublituximab.

Development of Optimized Strategy for Cloning, Expression and Analysis of a Recombinant Anti-CD20 Therapeutic Monoclonal Antibody in HEK-293 Cells

The significance of expression systems for quickly creating enough numbers of therapeutic monoclonal antibodies to make them available to patients has been heightened in recent years due to advances in the creation of genetically modified monoclonal antibodies. The conventional method for making recombinant proteins involves first cloning the desired gene into an expression vector, and then testing how well it expresses itself in cells. For cellular expression and perpetuation, a plasmid containing the chosen genes is then cloned. The most significant and lucrative subset of biopharmaceuticals is monoclonal antibodies (mAbs). To temporarily produce an anti-CD20 monoclonal antibody in mammalian cells, this work created and assessed an antiCD20 mAb expression construct. The gene fragment was transferred to the expression vector after the vector (pcDNA3.1+) was synthesised by sequentially cloning the Light Chain (LC) and Heavy Chain (HC). We co-transfected HEK 293 cells and then examined the cell culture supernatant for antibody clone expression. Using this technology to transiently express the whole monoclonal antibody in mammalian cells was a breeze, and our findings prove it.

Artificial Intelligence-Powered Molecular Docking and Steered Molecular Dynamics for Accurate scFv Selection of Anti-CD30 Chimeric Antigen Receptors.

Chimeric antigen receptor (CAR) T cells represent a revolutionary immunotherapy that allows specific tumor recognition by a unique single-chain fragment variable (scFv) derived from monoclonal antibodies (mAbs). scFv selection is consequently a fundamental step for CAR construction, to ensure accurate and effective CAR signaling toward tumor antigen binding. However, conventional in vitro and in vivo biological approaches to compare different scFv-derived CARs are expensive and labor-intensive. With the aim to predict the finest scFv binding before CAR-T cell engineering, we performed artificial intelligence (AI)-guided molecular docking and steered molecular dynamics analysis of different anti-CD30 mAb clones. Virtual computational scFv screening showed comparable results to surface plasmon resonance (SPR) and functional CAR-T cell in vitro and in vivo assays, respectively, in terms of binding capacity and anti-tumor efficacy. The proposed fast and low-cost in silico analysis has the potential to advance the development of novel CAR constructs, with a substantial impact on reducing time, costs, and the need for laboratory animal use.

A multi-centre longitudinal study analysing multiple sclerosis disease-modifying therapy prescribing patterns during the COVID-19 pandemic

BackgroundThe COVID-19 pandemic raised concern amongst clinicians that disease-modifying therapies (DMT), particularly anti-CD20 monoclonal antibodies (mAb) and fingolimod, could worsen COVID-19 in people with multiple sclerosis (pwMS). This study aimed to examine DMT prescribing trends pre- and post-pandemic onset.MethodsA multi-centre longitudinal study with 8,771 participants from MSBase was conducted. Two time periods were defined: pre-pandemic (March 11 2018–March 10 2020) and post-pandemic onset (March 11 2020–11 March 2022). The association between time and prescribing trends was analysed using multivariable mixed-effects logistic regression. DMT initiation refers to first initiation of any DMT, whilst DMT switches indicate changing regimen within 6 months of last use.ResultsPost-pandemic onset, there was a significant increase in DMT initiation/switching to natalizumab and cladribine [(Natalizumab-initiation: OR 1.72, 95% CI 1.39–2.13; switching: OR 1.66, 95% CI 1.40–1.98), (Cladribine-initiation: OR 1.43, 95% CI 1.09–1.87; switching: OR 1.67, 95% CI 1.41–1.98)]. Anti-CD20mAb initiation/switching decreased in the year of the pandemic, but recovered in the second year, such that overall odds increased slightly post-pandemic (initiation: OR 1.26, 95% CI 1.06–1.49; Switching: OR 1.15, 95% CI 1.02–1.29. Initiation/switching of fingolimod, interferon-beta, and alemtuzumab significantly decreased [(Fingolimod-initiation: OR 0.55, 95% CI 0.41–0.73; switching: OR 0.49, 95% CI 0.41–0.58), (Interferon-gamma-initiation: OR 0.48, 95% CI 0.41–0.57; switching: OR 0.78, 95% CI 0.62–0.99), (Alemtuzumab-initiation: OR 0.27, 95% CI 0.15–0.48; switching: OR 0.27, 95% CI 0.17–0.44)].ConclusionsPost-pandemic onset, clinicians preferentially prescribed natalizumab and cladribine over anti-CD20 mAbs and fingolimod, likely to preserve efficacy but reduce perceived immunosuppressive risks. This could have implications for disease progression in pwMS. Our findings highlight the significance of equitable DMT access globally, and the importance of evidence-based decision-making in global health challenges.

Local radiotherapy and measurable residual disease-driven immunotherapy in patients with early-stage follicular lymphoma (FIL MIRO): final results of a prospective, multicentre, phase 2 trial

The mainstay of treatment for early-stage follicular lymphoma is local radiotherapy, with a possible role for anti-CD20 monoclonal antibody (mAb). We aimed to evaluate the effect of these treatments using a measurable residual disease (MRD)-driven approach. This prospective, multicentre, phase 2 trial was conducted at 27 centres of the Fondazione Italiana Linfomi (FIL) in Italy. Eligible participants were adults (≥18 years) with newly diagnosed, histologically confirmed follicular lymphoma (stage I or II; grade I-IIIa). Patients were initially treated with 24 Gy involved-field radiotherapy over 12 days; those who were MRD-positive after radiotherapy or during follow-up received eight intravenous doses (1000 mg per dose; one dose per week) of the anti-CD20 mAb ofatumumab. The primary endpoint was the proportion of patients who were MRD-positive after involved-field radiotherapy and became MRD-negative after ofatumumab treatment. Patients were included in the primary endpoint analysis population if they were positive for BCL2::IGH rearrangement at enrolment in peripheral blood or bone marrow samples. MRD positivity was defined as the persistence of BCL2::IGH rearrangement in peripheral blood or bone marrow, assessed centrally by laboratories of the FIL MRD Network. The trial was registered with EudraCT, 2012-001676-11. Between May 2, 2015, and June 1, 2018, we enrolled 110 participants, of whom 106 (96%) were eligible and received involved-field radiotherapy. Of these, 105 (99%) were White, one (1%) was Black, 50 (47%) were male, and 56 (53%) were female. Of 105 participants in whom BCL2::IGH status was evaluable, 32 (30%) had a detectable BCL2::IGH rearrangement at baseline. After radiotherapy, 12 (40%) of 30 patients reached MRD-negative status, which was long-lasting (at least 36 or 42 months) in three (25%). In those who were MRD-positive after radiotherapy, ofatumumab induced MRD-negativity in 23 (92%; 95% CI 74-99) of 25 evaluable patients. After a median follow-up of 46·1 months (IQR 42·8-50·8), 14 (61%) of these 23 patients remain in complete response and are MRD-negative. The most common grade 3-4 adverse events were infusion-related reactions, observed in four patients. Local radiotherapy is frequently not associated with the eradication of follicular lymphoma. An MRD-driven, anti-CD20 monoclonal antibody consolidation enables molecular remission to be reached in almost all patients and is associated with a reduced incidence of relapse over time. A clinical advantage of an MRD-driven consolidation is therefore suggested. AIRC Foundation for Cancer Research in Italy, Novartis International, and GlaxoSmithKline.

Asciminib stands out as the superior tyrosine kinase inhibitor to combine with anti-CD20 monoclonal antibodies for the treatment of CD20+ Philadelphia-positive B-cell precursor acute lymphoblastic leukemia in preclinical models.

Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCPALL) is a high-risk acute lymphoblastic leukemia subtype characterized by the presence of BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKIs) combined with chemotherapy are established as the first-line treatment. Additionally, rituximab (RTX), an anti-CD20 monoclonal antibody (mAb) is administered in adult BCP-ALL patients with ≥20% of CD20+ blasts. In this study, we observed a marked prevalence of CD20 expression in patients diagnosed with Ph+ BCP-ALL, indicating a potential widespread clinical application of RTX in combination with TKIs. Consequently, we examined the influence of TKIs on the antitumor effectiveness of anti-CD20 mAbs by evaluating CD20 surface levels and conducting in vitro functional assays. All tested TKIs were found to uniformly downregulate CD20 on leukemic cells, diminishing the efficacy of RTX-mediated complement-dependent cytotoxicity. Interestingly, these TKIs displayed varied effects on NK cell-mediated antibody-dependent cytotoxicity and macrophage phagocytic function. While asciminib demonstrated no inhibition of effector cell functions, dasatinib notably suppressed the anti-CD20-mAb-mediated NK cell cytotoxicity and macrophage phagocytosis of BCP-ALL cells. Dasatinib and ponatinib also decreased NK cell degranulation in vitro. Importantly, oral administration of dasatinib, but not asciminib, compromised NK cell activity within patients' blood, determined by ex vivo degranulation assay. Our results indicate that asciminib might be preferred over other TKIs for combination therapy with anti-CD20 mAbs.

Efficacy, safety, and determination of RP2D of ABBV-383, a BCMA bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM).

7531 Background: MM eventually becomes refractory to current treatments, and new therapeutic options with convenient dosing and improved safety are needed to enhance patient (pt) adherence, access, and outcomes. ABBV-383 is a distinctive next-generation BCMA x CD3 bispecific antibody composed of 2 high-affinity BCMA-binding domains, a low-affinity CD3-binding domain designed to reduce cytokine release syndrome (CRS) risk, and a silenced Fc tail for an extended half-life allowing convenient dosing. ABBV-383 monotherapy has shown promising activity in the ongoing first-in-human phase 1 trial in RRMM (Vij et al. Blood 2023;142[suppl 1]:3378). Here, safety and efficacy results are reported that support the RP2D of 60mg Q4W as the optimal therapeutic ABBV-383 monotherapy dose. Methods: This phase 1 open-label, dose-escalation/expansion trial (NCT03933735) enrolled pts with RRMM who received ≥3 prior lines of therapy with exposure to PI, IMiD, and anti-CD38 mAb. ABBV-383 regimens explored in the expansion phase included 60mg Q4W and 40 or 60mg Q3W. A modified dexamethasone premedication schedule and shortened CRS monitoring period were implemented in the 60mg Q4W cohort for cycle 1. IV ABBV-383 was administered as a flat dose with no step-up schedule. Treatment was continued until disease progression/unacceptable toxicity. Primary objectives were to assess safety, tolerability, PK, PD, and determine the RP2D. Efficacy evaluation was a secondary objective. TEAEs were assessed per CTCAE v5.0 and tumor response per IMWG 2016 criteria. Results: As of May 2023, 220 pts received ABBV-383 (median age: 68 yr [35–92]; median prior therapy lines: 5 [3‒23]). Median FU was 4.1 mo (0.8–5.2) at 60mg Q4W (n=21), 12.2 mo (1.3–34.4) at 40mg Q3W (n=55), and 24.2 mo (0.6–33.4) at 60mg Q3W (n=61). At 60mg Q4W, with the modified premedication regimen, CRS was reported in 43% of pts (38% G1, 5% G2), and ICANS in 5% of pts (G2). In Q3W cohorts, CRS was reported in 71% (40mg; 45% G1, 25% G2) and 70% (60mg; 51% G1, 18% G2, 2% G3) of pts. The incidence of G3/4 neutropenia, anemia, and thrombocytopenia was 14/24/10% at 60mg Q4W, 31/31/16% at 40mg Q3W, and 34/13/13% at 60mg Q3W. G3/4 infections occurred in 10/24/34% of pts at 60mg Q4W, 40mg and 60mg Q3W, respectively. ORR and ≥VGPR were 65/50% at 60mg Q4W, 64/53% at 40mg Q3W, and 60/52% at 60mg Q3W. Corresponding exposure-response (ER) analyses and correlative analyses further supported RP2D determination (separate abstract submissions). Conclusions: The optimal therapeutic dose of 60mg Q4W ABBV-383 monotherapy was selected on the basis of safety, efficacy, and ER analyses. The extended interval of Q4W, with a shortened CRS monitoring period in cycle 1 and no step-up dosing, will improve convenience and reduce the treatment burden for pts. ABBV-383 at 60mg Q4W will be investigated in the registrational phase 3 trial (NCT06158841) in RRMM. Clinical trial information: NCT03933735 .

Phase I safety and preliminary efficacy of IMM0306 in combination with lenalidomide in patients with relapsed or refractory CD20-positive B-cell non-Hodgkin's lymphoma.

e19040 Background: The combination of rituximab (anti-CD20 mAb) and lenalidomide was approved for use in relapsed or refractory (R/R) indolent non-Hodgkin's lymphoma (iNHL). IMM0306 is a fusion protein of CD20 monoclonal antibody with the CD47 binding domain of SIRPα on both heavy chains. It exerts excellent cancer killing efficacy by activating both macrophages and NK cells via blockade of CD47-SIRPα interaction and FcɣR engagement. Here, we report on a Phase I study of 8 patients (pts) with R/R CD20-positive B-cell NHL. Methods: This is an open-label, multicenter phase I study (NCT05771883). The study is designed to use "3+3" scheme for dose escalation exploring in 2 dose levels of IMM0306 (1.6 mg/kg, 2.0 mg/kg), intravenously administered each week in each 28-day cycle; while lenalidomide will be administered as fixed dose of 20 mg for NHL, taken orally once daily for the first 21 days of each 28-day cycle to determinate maximum tolerated dose (MTD). Dose-limiting toxicity (DLT) was evaluated in the first 28 days of the combination therapy. Safety was evaluated per CTCAE 5.0, tumor assessments performed once every 8 weeks by Lugano 2014. Results: As of Jan 5, 2024, 8 pts with R/R follicular lymphoma (FL, n=6) and marginal zone lymphoma (MZL, n=2) were enrolled. The median age was 52.5 years with 7 (87.5%) males. The median prior line of therapy was 1. All pts received previous anti-CD20 therapy. Among 7 efficacy evaluable pts, 1 CR (FL), 4 PR (2 FL, 2 MZL), and 1 SD were seen. The ORR and DCR were 71.4% and 85.7%, respectively. Two DLTs (grade 4 PLT decreased without bleeding) were observed at 2.0 mg/kg IMM0306 + 20 mg Lenalidomide dose level, but none at the dose level of 1.6 mg/kg IMM0306 + 20 mg Lenalidomide. The most common treatment related adverse events (TRAEs) were lymphocyte decreased (62.5%), ANC decreased (62.5%), WBC decreased (50%), anemia (50%), bilirubin increased (50%), PLT decreased (37.5%), infusion-related reactions (37.5%). Grade ≥3 TRAEs occurred in 6 pts, including lymphocyte decreased (62.5%), PLT decreased (25%), WBC decreased (12.5%), ANC decreased (12.5%) and pneumonia (12.5%). One pt experienced treatment related serious adverse event. 5 patients experienced TRAEs, leading to the study drug interruption, while no patients experienced TRAEs leading to the study drug discontinuation or death. 2 pts had a dose reduction of IMM0306 (2.0 mg/kg dose level), 3 pts had dose reductions of lenalidomide due to TRAEs. Pharmacodynamics analysis demonstrated IMM0306 combine lenalidomide effectively depleted B cell in peripheral blood within 24 hours. Conclusions: 1.6 mg/kg IMM0306 in combination with 20 mg lenalidomide was well-tolerated and with a robust preliminary anti-tumor activity in pts with R/R FL and MZL. The phase I study is ongoing. Clinical trial information: NCT05771883 .

Evaluating CR as a surrogate endpoint for PFS in R/R chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): A meta-analysis of randomized controlled trials (RCT).

7046 Background: CLL/SLL is the most common leukemia in adults. Achieving a CR by International Workshop on CLL 2018 criteria indicates complete eradication of CLL/SLL in all disease compartments. Patients with R/R CLL/SLL who achieved CR tend to have delayed disease progression/death compared with patients who did not achieve CR. This is the first report to evaluate CR as a surrogate endpoint for PFS in R/R CLL/SLL using aggregate RCT data. Methods: A systematic literature review (SLR) identified published RCTs in R/R CLL/SLL from inception to 10/2023, reporting nonzero CR rates (CRR) and PFS. Association between treatment effects on CR and PFS across RCTs was estimated using a weighted linear model (WLM) in the primary analysis, and Daniels and Hughes (D&amp;H) and Riley bivariate random-effects meta-analysis (BRMA) in sensitivity analyses. Strength of association was assessed based on surrogacy criteria described by D&amp;H. Predictive performance of models was evaluated using leave-one-out cross-validation. Results: The SLR identified 13 RCTs with a total of 4388 patients with R/R CLL/SLL treated with a variety of therapies, including but not limited to BTKi, BCL2i, PI3Ki, CAR T cell therapy, anti-CD20 mAb, and chemotherapy. Across the evidence base, CRR ranged from 0.48% to 38.10% and median PFS was between 1 and 35.9 months (excluding unreached medians). Across RCTs, contrasting treatment and control arms, higher odds of CR resulted in lower hazards of disease progression/death (CRR improvement translated to PFS benefit). D&amp;H surrogacy criteria were met for WLM: 1) a near-zero, statistically nonsignificant intercept, indicating that no treatment effect on CRR implies no effect on PFS; 2) a negative, statistically significant slope, suggesting that improved CRR correlates with longer PFS; and 3) a near-zero conditional variance, meaning that PFS HR variation was primarily explained by CR odds ratio. During cross-validation, treatment effects on CR were predictive of PFS benefits, as the 95% predictive interval of PFS HR contained the observed HR in all RCTs for WLM. Results were largely consistent across all 3 models(Table). Conclusions: Improved CRR corresponds to prolonged PFS across RCTs and treatment comparisons. The results support CRR as an important treatment goal for R/R CLL/SLL and a valid surrogate endpoint. Consistent results and predictive performance across different models indicate the robustness of the results. [Table: see text]