This is an open-label, multicenter, Phase I/II study designed to evaluate the safety, tolerability, pharmacokinetic characteristics, and preliminary efficacy of EMB-07 combination therapy in adult patients with aggressive B-cell non-Hodgkin lymphoma (B-NHL). The study consists two phases: Phase I of dose escalation and Phase II of dose expansion. Approximately 115 patients will be enrolled in this study (i.e., 5 cohorts of approximately 23 patients per cohort). Multiple EMB-07-based combination regimens will be evaluated in patients with relapsed/refractory (R/R) aggressive B-NHL (Cohort A) and patients with newly diagnosed aggressive B-NHL (Cohort B).

Inclusion Criteria:

1. Ability to understand and voluntarily sign the Informed Consent Form (ICF);
2. Patients aged ≥18 years;
3. Life expectancy > 12 weeks;
4. ECOG performance status score: ≤1 point during the dose escalation phase, ≤2 points during the dose expansion phase.
5. Cohort A: Pathologically confirmed aggressive R/R B-NHL, including DLBCL, not otherwise specified (NOS), or DLBCL transformed from indolent lymphoma (e.g., follicular lymphoma) (t-DLBCL), or other aggressive B-NHL judged to potentially benefit from study treatment by the investigator and sponsor (e.g., high-grade B-cell lymphoma [HGBL], Richter transformation, other large B-cell lymphoma subtypes).

Cohort B: Newly diagnosed, treatment-naïve DLBCL NOS confirmed by pathology, or t-DLBCL not previously treated with adequate (at least 2 cycles) R-CHOP therapy (excluding Richter transformation or HGBL with BCL2/MYC±BCL6 rearrangements). Patients with newly diagnosed DLBCL NOS should have an International Prognostic Index (IPI) score ≥2 and Ann Arbor stage ≥2. The sponsor will reserve the right to limit the number of t-DLBCL patients enrolled in the study. Other aggressive B-NHLs patients who may benefit from the study treatment can be enrolled after careful risk/benefit assessment by the sponsor and investigator.

Exclusion Criteria:

1. Current or prior central nervous system (CNS) or meningeal involvement related to the underlying disease.

2. Cohort A: Prior exposure to any ROR1-targeted agent (e.g., biologic or CAR-T); or Cohort A1: Prior exposure to Gemcitabine-based chemotherapy (≥ 2 consecutive cycles); or Cohort A2: Prior exposure to Polatuzumab Vedotin; or Cohorts A3 and A4: Refractory to prior Lenalidomide/Zanubrutinib or Chidamide therapy, respectively.

3. Contraindications to any agent included in the combination therapy regimen.

4. Cohort A: Candidates suitable for ASCT or CAR-T cell therapy.

5. Cohort A: Use of any standard or investigational therapy for the underlying disease within 28 days before C1D1 or 5 half-lives (whichever is shorter), including chemotherapy, immunotherapy, radioimmunotherapy, non-palliative radiotherapy, or any other anti-tumor therapy. Only palliative radiotherapy to non-target lesions will be permitted.

6. Cohort B: B-NHL with prior receipt of at least 2 consecutive cycles of R-CHOP (prior lymph node biopsy or local radiotherapy will not be an exclusion criterion).

7. Major surgery or live vaccine administration within 28 days prior to C1D1.

8. History of allogeneic hematopoietic stem cell transplantation or solid organ transplantation (except corneal transplantation). In addition, patients who received ASCT within 3 months before C1D1, CAR-T within 6 months before C1D1, or diagnosed with graft-versus-host disease (GVHD) will be excluded.

9. Any AE related to prior therapy (excluding alopecia) that has not resolved to Grade ≤ 1 (per the Common Terminology Criteria for Adverse Events [CTCAE], Version 5.0) or baseline at C1D1.

10. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening. Patients with positive HBsAg and/or positive HBcAb but negative HBV DNA will be eligible for enrollment. Patients with positive HCV antibody but negative HCV RNA are also eligible for enrollment.

11. Known positive HIV serology or history of active viral infection

12. Active infection requiring parenteral antibiotics, antivirals, or antifungals within 14 days before C1D1; prophylactic use of these agents (including parenteral administration) will be permitted.

13. Prior malignancy requiring treatment or with evidence of recurrence within 5 years before C1D1 (except non-melanoma skin cancer or adequately treated carcinoma in situ of the cervix). Patients with a history of cancer treated with curative intent > 5 years before C1D1 and no evidence of recurrence will be eligible.

14. Ischemic or hemorrhagic stroke of Grade ≥ 3, or gastrointestinal bleeding of Grade ≥ 3, within 6 months before C1D1.

15. Active, unstable cardiovascular function:

    • Myocardial infarction within 6 months before C1D1;
    • Unstable angina within 3 months before C1D1;
    • Clinically significant uncontrolled arrhythmias (e.g., sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes);
    • Mobitz type II second-degree or third-degree atrioventricular block;
    • Congestive heart failure at class ≥ 3 per New York Heart Association (NYHA)
    • Known left ventricular ejection fraction (LVEF) < 50%.

16. Known or suspected history of hemophagocytic lymphohistiocytosis (HLH);

17. Known history of progressive multifocal leukoencephalopathy;

18. Active autoimmune disease requiring treatment

    • Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid hormone replacement will be eligible.
    • Type 1 diabetes mellitus well-controlled with insulin therapy will be permitted.
    • Patients with a history of autoimmune hepatitis, systemic lupus erythematosus, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, granulomatosis with polyangiitis, Sjögren's syndrome, multiple sclerosis, or glomerulonephritis will be excluded.
    • Patients with a history of immune thrombocytopenic purpura, autoimmune hemolytic anemia, Guillain-Barré syndrome, myasthenia gravis, myositis, rheumatoid arthritis, vasculitis, or other autoimmune diseases are excluded unless no systemic therapy has been required in the past 12 months.

19. Prior systemic immunosuppressive medication (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 28 days before C1D1.

20. Systemic corticosteroid use within 2 weeks before study treatment at a dose equivalent to > 10 mg/day Prednisone. Inhaled, topical, or ophthalmic steroids will be permitted. Short-term corticosteroid use (e.g., prophylaxis for intravenous contrast) will be permitted.

21. Any other severe underlying medical condition (e.g., active gastric ulcer, uncontrolled seizures, cerebrovascular event, gastrointestinal bleeding, coagulation/thrombotic disorders with severe signs/symptoms, cardiac disease), or psychiatric, psychological, familial, or geographic factors that, in the investigator's judgment, possibly interfere with scheduled disease assessments, treatment, and follow-up, compromise patient compliance, or place the patient at high risk of treatment-related complications.

22. Female patients who are pregnant or breastfeeding. Abuse of alcohol, cannabis-derived products, or other controlled substances.